pressure ulcer research

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Pressure Ulcer Research D. Bader ´ C. Bouten ´ D. Colin ´ C. Oomens (Eds.)

Dan Bader ´ Carlijn Bouten Denis Colin ´ Cees Oomens

Pressure Ulcer Research Current and Future Perspectives

With 76 Figures and 23 Tables

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Dan L. Bader, PhD, DSc Queen Mary University of London Mile End Road London E1 4NS United Kingdom Carlijn V. C. Bouten, PhD Eindhoven University of Technology Biomedical Engineering Department Den Dolech 2, P/O Box 513 5600 MB Eindhoven The Netherlands Denis Colin, MD Medical Director Centre de l'Arche 72650 Saint Saturnin Le Mans, France Cees W. J. Oomens, PhD Eindhoven University of Technology Biomedical Engineering Department Den Dolech 2, P/O Box 513 5600 MB Eindhoven The Netherlands

ISBN-10 3-540-25030-1 Springer Berlin Heidelberg New York ISBN-13 978-3-540-25030-2 Springer Berlin Heidelberg New York Library of Congress Control Number: 2005928443 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from SpringerVerlag. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science+Business Media springeronline.com ° Springer-Verlag Berlin ´ Heidelberg 2005 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Editor: Gabriele Schræder, Springer-Verlag Desk Editor: Stephanie Benko, Springer-Verlag Production: Pro Edit GmbH, Elke Beul-Gæhringer, Heidelberg, Germany Typesetting: K+V Fotosatz GmbH, Beerfelden Cover design: Estudio Calamar, F. Steinen-Broo, Pau/Girona, Spain 24/3151/beu-gæh ± 5 4 3 2 1 0 ± Printed on acid-free paper

. . . In the morning she was asked how she had slept. ªOh, very badly!º said she. ªI have scarcely closed my eyes all night. Heaven only knows what was in the bed, but I was lying on something hard, so that I am black and blue all over my body. It's horrible!º Now they knew she was really a princess because she had felt the pea right through the twenty mattresses and the twenty eider-down beds . . . (Hans Christian Andersen: The Princess & The Pea) We dedicate this book to all the princesses and princes in the world

Preface

Although the clinical condition of pressure ulcers has existed since time immemorial, with evidence of its occurrence in ancient Egypt, there has been a paucity of tomes devoted to the subject. Of the few which have highlighted the scientific aspects of the topic, two edited books, ªBed Sore Biomechanicsº [1] and ªPressure Sores ± Clinical Practice and Scientific Approachº [2] were published around 30 and 15 years ago, respectively. It is interesting to note that the name of the condition has changed during this period, from bed sores to pressure sores to pressure ulcers. The current term has been widely adopted worldwide by various organisations, such as the National Pressure Ulcer Advisory Panel (NPUAP) in the USA, the EPUAP in Europe and the Japanese Pressure Ulcer Society. Each body is committed to prevention and treatment strategies, but despite their efforts incidence figures remain unacceptably high. So what was our motivation for the current book? Well, we have already invested many years, with only minor success, in trying to alleviate this horrendous condition, which Pam Hibbs regularly described as ªthe hidden epidemic beneath the sheetsº. However, as in most walks of life, politics and monetary considerations have reared their heads. As an example, a financial audit in 1997 in the Netherlands encompassing all clinical conditions revealed that the prevention and treatment of pressure ulcers represented the fourth largest financial burden on the Dutch health service. This stimulated a wealth of activity in the Biomedical Engineering Department at the Technological University of Eindhoven, which brought us, the editors, together. In addition, the medico-legal implications of ulcer development have stimulated the interests of financial managers, who run hospitals and homes, and the associated medical insurance companies. Further considerations involve conditions that previously were life threatening but now are manageable with the advances in medical technologies. This has resulted in an ever-ageing population in many countries. It is only right for every individual to demand an improved healthspan to match this increased lifespan. Again, technology can provide solutions, and, as researchers, we firmly believe that much can be gained from applying many of the new sciences, ranging from genomics over cellular and tissue engineering to medical imaging and computational modelling. These tools can be used to provide a clearer understanding of the mechanisms associated with the aetiology of pressure ulcers, extending beyond the conventional wisdom of the effects of pressure ischaemia alone. Ultimately, they will also be used to identify the risk

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levels of individuals and provide appropriate support systems. This was the motivation for us to bring together a number of multidisciplinary world experts, who have contributed generously to this volume. The Editors

References 1. Kenedi RM, Cowden JM, Scales JT (eds) (1976) Bed sore biomechanics. Macmillan, London 2. Bader DL (ed) (1990) Pressure sores: clinical practice and scientific approach. Macmillan, London

Contents

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The Aetiopathology of Pressure Ulcers: A Hierarchical Approach . . . . Carlijn Bouten, Cees Oomens, Denis Colin, Dan Bader

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Medical Perspectives in the 21st Century . . . . . . . . . . . . . . . . . . . . Jeen Haalboom

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Medico-Legal Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Courtney Lyder

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Patients at Risk for Pressure Ulcers and Evidence-Based Care for Pressure Ulcer Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nancy Bergstrom

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The Measurement of Interface Pressure . . . . . . . . . . . . . . . . . . . . . Ian Swain

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Susceptibility of Spinal Cord-Injured Individuals to Pressure Ulcers . . Kath Bogie, Dan Bader

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Prevention and Treatment of Pressure Ulcers Using Electrical Stimulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thomas Janssen, Christof Smit, Maria Hopman

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Biochemical Status of Soft Tissues Subjected to Sustained Pressure . 109 Dan Bader, Yak-Nam Wang, Sarah Knight, Adrian Polliack, Tim James, Richard Taylor

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Stump±Socket Interface Conditions . . . . . . . . . . . . . . . . . . . . . . . . . Joan Sanders

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Contents

10 Perspectives of Numerical Modelling in Pressure Ulcer Research . . . . Cees Oomens 11 Skin Morphology and Its Mechanical Properties Associated with Loading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Satsue Hagisawa, Tatsuo Shimada 12 Compression-Induced Tissue Damage: Animal Models . . . . . . . . . . . . Anke Stekelenburg, Cees Oomens, Dan Bader 13 The Role of Oxidative Stress in the Development and Persistence of Pressure Ulcers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Richard Taylor, Tim James

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14 Transport of Fluid and Solutes in Tissues . . . . . . . . . . . . . . . . . . . . Charles Michel

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15 Skin Model Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yak-Nam Wang, Joan Sanders

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16 In Vitro Muscle Model Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . Debby Gawlitta, Carlijn Bouten

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17 Imaging Tissues for Pressure Ulcer Prevention . . . . . . . . . . . . . . . . . Martin Ferguson-Pell

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18 Magnetic Resonance Imaging and Spectroscopy of Pressure Ulcers . . Gustav Strijkers, Jeanine Prompers, Klaas Nicolay

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19 Microelectrodes and Biocompatible Sensors for Skin pO2 Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Wen Wang, Pankaj Vadgama

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20 New Tissue Repair Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Debbie Bronneberg, Carlijn Bouten

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Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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List of Contributors

Dan Bader Department of Engineering & IRC in Biomedical Materials Queen Mary University of London Mile End Road London, E1 4NS UK Nancy Bergstrom Center on Aging 6901 Bertner Avenue, 625 Houston, TX 77030, USA Kath Bogie Rehabilitation Engineering Center Cleveland FES Center Hamann Building, Room 601 MetroHealth Medical Center 2500 MetroHealth Drive Cleveland, OH 44109-1998 USA Carlijn Bouten Biomedical Engineering Department Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands Debbie Bronneberg Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands

Denis Colin Rehabilitation Hospital Centre de l'Arche 72650 Saint Saturnin France Martin Ferguson-Pell Centre for Disability Research and Innovation Institute of Orthopaedics & Musculo-Skeletal Science University College London RNOH Trust Brockley Hill, Stanmore Middlesex, HA7 4LP UK Debby Gawlitta Biomedical Engineering Department Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands Jeen Haalboom Universitair Medisch Centrum Utrecht Interne Geneeskunde P.O. Box 85500 3508 GA Utrecht The Netherlands Satsue Hagisawa Department of Nursing Kumamoto Health Science University Izumi 325 Kumamoto 861-5598 Japan

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Maria Hopman Radboud University Nijmegen Medical Centre Department of Physiology Nijmegen The Netherlands

Cees Oomens Biomedical Engineering Department Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands

Tim James Department of Clinical Biochemistry Oxford Radcliffe Hospital Headington Oxford, OX3 1XX UK

Adrian Polliack Department of Clinical Biochemistry Oxford Radcliffe Hospital Headington Oxford, OX3 1XX UK

Thomas Janssen Faculty of Human Movement Sciences Vrije Universiteit Van der Boechorststraat 9 1081 BT Amsterdam The Netherlands

Jeanine Prompers Department of Biomedical Technology Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands

Sarah Knight Spinal Research Centre Royal National Orthopaedic Hospital Brockley Hill Stanmore, Middlesex, HA7 4LP UK

Joan Sanders Bioengineering, 357962 University of Washington Seattle, WA 98195 USA

Courtney Lyder School of Nursing University of Virginia McLeod Hall Charlottesville, VA 22908 USA Charles Michel Imperial College London South Kensington Campus London, SW7 2AZ UK Klaas Nicolay Department of Biomedical Technology Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands

Tatsuo Shimada School of Nursing Oita University Hasama 1-1, Oita 879-5593 Japan Christof Smit Rehabilitation Center Amsterdam Overtoom 283 1054 HW Amsterdam The Netherlands Anke Stekelenburg Biomedical Engineering Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands

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Gustav Strijkers Department of Biomedical Technology Eindhoven University of Technology P/O Box 513 5600 MB Eindhoven The Netherlands

Pankaj Vadgama IRC in Biomedical Materials Queen Mary University of London Mile End Road London, E1 4NS UK

Ian Swain Department of Medical Physics & Biomedical Engineering Salisbury District Hospital Salisbury Wiltshire, SP2 8BJ UK

Wen Wang Medical Engineering Division Department of Engineering Queen Mary University of London Mile End Road London E1 4NS UK

Richard Taylor Department of Clinical Biochemistry Oxford Radcliffe Hospital Headington Oxford, OX3 9DU UK

Yak-Nam Wang Department of Bioengineering 357962, Harris 309 University of Washington Seattle, WA 98195 USA

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The Aetiopathology of Pressure Ulcers: A Hierarchical Approach 1

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Carlijn Bouten, Cees Oomens, Denis Colin, Dan Bader

Introduction Pressure ulcers are localized areas of tissue breakdown in skin and/or underlying tissues [1]. They can occur in all situations where subjects are subjected to sustained mechanical loads, but are particularly common in those who are bedridden, wheelchair bound or wearing a prosthesis or orthosis. The ulcers are painful, difficult to treat, and represent a burden to the community in terms of healthcare and finances. Consequently, they may affect the quality of life of many young and elderly individuals. To date, attempts to prevent pressure ulcers have not led to a significant reduction of the problem. As is detailed in Chaps. 2 and 3, prevalence figures remain unacceptably high, ranging between 8 and 23% depending on the severity of wounds included and the subject group under investigation [2± 4]. It is widely established that this is, at least partly, due to the limited fundamental knowledge related to the aetiology of the clinical condition. Thus, the design and application of preventive aids and risk assessment techniques are so far dominated by subjective measures or, at best, based on a relatively small amount of data focusing on skin tissues. A striking example is the traditionally quoted value for capillary closure pressure of 32 mmHg (4.3 kPa) that is still frequently used as a threshold for tissue damage [5]. Interface pressures at the contact area between skin and supporting surfaces (such as mattresses or cushions) in excess of this value are assumed to produce a degree of ischaemia which, if applied for a sufficient period of time, may lead to tissue breakdown [6±8]. Leaving aside the discussion of whether ischaemia is the principal factor for tissue breakdown in pressure ulcers, capillary closure depends on local pressure gradients across the vessel wall and not just on interface pressures at the skin level. Hence interface pressures well above capillary pressures can be supported by the soft tissues before blood flow is seriously impaired [9]. An interesting observation reported by Husain [10] in 1953 was that localized interface pressures obliterated more vessels in the skin and subcutaneous tissue than in the muscle, while the latter was severely damaged and 1

The content of this chapter is based on the authors' paper: ªThe aetiology of pressure sores: skin deep or muscle bound?º (Arch Phys Med Rehab 84:616± 619; 2003) [39].

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the skin and subcutis were not. Later studies also demonstrated that muscle tissue is more susceptible to mechanical loading than skin [6, 11, 12]. Notwithstanding these facts the primary focus in pressure ulcer prevention and treatment has traditionally been on skin, and the risks of tissue degeneration in other tissues is generally neglected. This is to a large extent due to the availability and possibilities of existing methodologies and technologies, which limited the aetiological knowledge progression of pressure ulcer development to the skin. In order to be able to reduce the prevalence of pressure ulcers it is essential to improve and expand our knowledge of the aetiopathogenesis in terms of both basic science and clinical application. In terms of the former we propose a more rigorous analysis of existing data, followed by a hierarchical research approach in which the effects of mechanical loading are studied at different tissue levels and at the level of different functional units of soft tissues. Tissue levels refer to superficial (skin) and/or deep tissue layers (muscle, subcutaneous fat), whereas tissue units involve the cells and extracellular matrix composing the tissue as well as the vessels providing for fluid transport inside the tissue. The separate tissues and tissue units and their relevance in pressure ulcer development are reviewed in detail in various chapters of this book. An integrated approach, combining the presented knowledge and proposed (new) research technologies, should lead to a thorough understanding of the aetiopathology and subsequent prevention and treatment of pressure ulcers.

Deep Versus Superficial Ulcers As a guide to pressure ulcer prevention, research has focused on determining the minimal degree of loading that will consistently lead to persistent tissue damage. Typically, such physical conditions are derived from animal experiments [6, 8, 13, 14] with some degree of variable control, and, more rarely, from human studies, the most prominent of which is nearly 30 years old but still regularly quoted [15]. In the animal studies soft tissues are loaded externally via prescribed pressures or shear stresses applied to the skin, whereas the onset of tissue breakdown is generally observed from histological examinations after predetermined periods of time, as is detailed in Chaps. 12 and 15. Despite large variations in absolute measures these studies all demonstrate an inverse relationship between the magnitude and duration of loading, indicating that the higher loads require less time to initiate tissue breakdown. More importantly, they suggest that pressure ulcers can develop either superficially or from within the deep tissue depending on the nature of the surface loading. The superficial type forms in the skin with maceration and detachment of superficial skin layers and is predominantly caused by shear stresses within the skin layers. If allowed to progress the damage may form an ulcer, which is easily detected [13, 16]. Deep ulcers, on the other hand, arise in deep muscle layers covering

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bony prominences and are mainly caused by sustained compression of the tissue [6, 8, 10, 12, 17]. These ulcers are very harmful, developing at a faster rate than superficial ulcers and yielding more extensive ulceration. The damage progresses towards the surface, so that considerable necrosis of muscle, fascia and subcutaneous tissue may occur even at a stage when the skin shows only minor signs of tissue breakdown. Hence the initial pathological changes which lead to the most severe ulcers are in the deep tissues and therefore are difficult to identify with techniques currently available. Although this is recognized in clinical practice, where tactile examinations are prescribed to examine the tissue for deep pressure ulcers [19±21], this fact is frequently overlooked by objective risk assessment techniques, clinical classification schemes and techniques for prevention, such as those reviewed in Chap. 4, most of which focus on the skin and ignore the underlying tissues. Although these approaches have relevance in clinical practice because the skin is easily accessible, it should be realized that by the time a deep pressure ulcer becomes visible clinical intervention is too late and the prognosis is variable.

Pathways of Tissue Breakdown Although it is well acknowledged that pressure ulcers are primarily caused by sustained mechanical loading of the soft tissues of the body, prevention of the ulcers by reducing the degree of loading alone remains difficult. This is mainly due to the fact that the underlying pathways whereby mechanical loading leads to tissue breakdown are poorly understood. It is not clear how global, external loading conditions are transferred to local stresses and strains inside the tissues and how these internal conditions may ultimately lead to tissue breakdown at a cellular level. Considerable efforts have been made to determine the most effective way of measuring and reducing surface pressures at skin level [22, 23], as is also reviewed in Chap. 5. However, surface pressures are not representative of the internal mechanical conditions inside the tissue, which are most relevant for tissue breakdown. This is especially the case when tissue geometry and composition are complex and surface pressures result in highly inhomogeneous internal mechanical conditions, as is the case adjacent to bony prominences, like the trochanter, the sacrum, the heel or the ischial tuberosities. Nonetheless, in order to study the response of various tissue layers to mechanical loading the local mechanical environment within these layers needs to be known. The transition from global external loads to local internal stresses and strains requires the use of computer models [24, 25] (Chaps. 9 and 10) typically unfamiliar to experimentalists and clinical and nursing staff. Although not yet clinically validated these models may provide better insights into the mechanical conditions of separate tissue layers, extending from skin to muscle tissue. As an example, Fig. 1.1 shows a simplified computer model of the mechanical response of the sep-

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arate soft tissue layers in the human buttock during sitting on a foam cushion. The ischial tuberosity is simulated by an undeformable bony indenter, whereas representative visco-elastic mechanical properties are incorporated for the individual tissue layers and the cushion material [26]. Using the finite element approach, detailed information on the magnitude and location of internal stresses and strains as a result of external loading can be obtained. Figure 1.1 clearly shows the inhomogeneous mechanical condition of the various tissue layers and areas of large tissue strains in the deeper fat and muscle layers. Combining such models with experimental data on the load-bearing capacity of the individual tissue layers will provide predictive measures of when and where tissue damage is likely to occur. This is, however, not straightforward, since the load-bearing capacity of the biological tissues is influenced by many systemic and local factors, such as temperature, nutritional status and disease. Although computer models will provide insight into the internal mechanical conditions relevant for tissue damage, experimental research is required to validate material properties and to explain how these conditions eventually lead to tissue breakdown. There is surprisingly little consensus about the pathophysiological response to mechanical loading that triggers soft tissue breakdown. Theories involve localized ischaemia [6±8, 13], impaired interstitial fluid flow and lymphatic drainage [23, 27, 28], reperfusion injury [29, 30] and sustained deformation of cells [14, 31]. Traditionally, these theories have been proposed following experimental observations limited to the depth of skin layers determined by the physical characteristics derived from such measurement techniques as that involving blood flow and oxygen tension. However, with the development of new techniques, including magnetic resonance imaging (MRI; Chap. 18), it is cer-

Fig. 1.1. Simplified computer model of deformed buttock (top left) of an 80-kg male subject demonstrating the differential response of the separate soft tissue layers (right) during sitting on a foam cushion. Because of assumed symmetry only half a buttock is used for calculations. Values indicate tissue strains, representing distortional energy. Note the areas of high strain in the subcutaneous fat and deep muscle layers (arrows) (adapted from [39])

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tainly possible to relate mechanical loading to pathophysiological phenomena within deeper tissues [32, 33]. Theories focusing on ischaemia and impaired lymphatic drainage have been studied in vivo and generally confirm that sustained tissue loading will influence tissue perfusion and/or lymph flow, thereby affecting the transport of nutrients to and metabolic waste products away from cells within the tissue. Although this is appropriate for muscle tissue, which is metabolically more active than skin, these theories can only partly explain the onset of pressure ulcers and have not been fully verified. The same argument also applies to reperfusion injury mediated through oxygen free radicals. This theory states that it is the restoration of blood flow after load removal, rather than impaired blood flow during loading per se, which exacerbates the compromise to the tissue viability. Although described for other post-ischaemic pathologies, such as cardiac infarction, the specific role of reperfusion injury in the causation of pressure ulcers is still the subject of extensive study (Chap. 12). However, if reperfusion injury is indeed an important factor in promoting pressure ulcers, many traditional clinical practices involving patient-turning and pressure-relieving systems need to be carefully evaluated. Existing histopathological data [14, 34] suggest a cellular origin of pressure ulcer development and it has been hypothesized that cellular damage is caused by sustained cell deformation. Indeed, cell deformation triggers a variety of effects, such as volume changes and cytoskeletal reorganization, which may be involved in early tissue breakdown. As it is impossible to examine the cellular response to loading in vivo independently of other factors, in-vitro models of cultured cells or engineered tissues under compressive or shear loading have been employed [35, 36]. Recent studies, described in Chaps. 15 and 16, demonstrate that such models are useful in studying the damaging effects of well-controlled compressive loading regimens in terms of cell damage or death. Although in-vitro models may prove to be an important tool in defining thresholds for cellular breakdown they are, as yet, difficult to relate to patient studies. Overall the existing theories focus on the different functional units of soft tissue, involving the cells, the interstitial space with extracellular matrix, and blood and lymph vessels. These units are affected by mechanical loading to varying degrees and hence have different relevance for tissue breakdown. Most probably each of them contributes to the causation of pressure ulcers, although their individual and combined role in tissue breakdown will undoubtedly vary depending on the nature of the mechanical insult and patient characteristics such as illness or age [37], which affect soft tissue properties and hence the vulnerability to tissue breakdown.

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Hierarchical Approach To investigate the differential response of the various tissue functional units to mechanical loading and their relative contributions to the development of pressure ulcers a hybrid methodology involving a combination of computational and experimental studies must be adopted. The experimental studies should aim at elucidating the relationships between mechanical loading, the pathophysiological response to loading and tissue breakdown in testing hypotheses on the aetiopathogenesis of pressure ulcers. The computational models should be designed to predict the association between external and internal mechanical conditions within soft tissues and their functional units. This methodology must incorporate all soft tissue layers involved in pressure ulcers, extending from superficial stratum corneum of the epidermis to dermal layers, to subcutaneous fat, fascia, and deep muscle layers. Moreover, a hierarchical approach is proposed, in which the effects of loading are studied in different, yet complementary, model systems with increasing complexity and length scale and incorporating one or more functional tissue units. Thus, in-vitro models, ranging from the single cell (micrometer scale) to cell-matrix constructs (millimeter scale) and individual tissue layers (millimeter-centimeter scale) might be used to study the relationship between cell deformation and cell damage [38], as well as the influence of the surrounding extracellular matrix and three-dimensional tissue architecture on this relationship. The role of tissue (re)perfusion and lymph flow as well as the interaction between tissue layers in bulk tissue might further be assessed using in-vivo studies with animal models or human subjects. The different length scales of these models can be coupled by multi-scale computer calculations that enable the prediction of the internal microscopic mechanical environment within a given model from global, macroscopic loading conditions, such as interface pressures (and vice versa). In this way relationships between, for instance, cell deformation and cell damage [36] can be extrapolated to the level of bulk tissue to give clinically relevant predictions on tissue breakdown. After setting the scene of pressure ulcer-related medical perspectives, costs and medico-legal aspects in Sect. 1, the proposed hierarchical approach is reflected in the chapters of Sects. 2 and 3. This approach can strongly benefit from new technologies, such as cell and tissue engineering and vital imaging techniques including MRI or vital microscopy, which are reviewed in Sect. 4. Cell and tissue engineering strategies enable the fabrication of in-vitro model systems with well-defined, controllable properties, which are designed to test specific hypotheses independently of predisposing factors associated with the onset of pressure ulcers. Vital imaging techniques permit monitoring of the pathophysiological response to loading in real time with none of the ethical considerations associated with the histological examination of loaded tissue in animal studies. Moreover, these techniques offer the potential of both examining the effects of mechanical loading in human subjects and, ultimately, serving as predictive tools for

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the screening of tissues for superficial or deep pressure ulcers in a clinical setting. Despite the considerable amount of existing clinical experience, it is our opinion that the proposed hierarchical approach will improve fundamental knowledge about the aetiopathology of pressure ulcers, which can serve as a sound basis for effective clinical identification and prevention. The hierarchy of model systems can be used to establish well-defined thresholds for tissue damage, which can provide new guidelines for pressure ulcer prevention and to redirect available pressure-relieving strategies. In addition, the established thresholds can be related to biochemical markers for the identification of early, reversible tissue damage. Adequate guidelines for damage prevention and early identification of damage will lead to a reduction of medical costs and time of hospitalisation, as well as a more efficient and economic use of available support systems.

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35. Landsman AS, Meaney DF, Cargill RS, Macarak EJ, Thibault LE (1995) High strain rate tissue deformation. A theory on the mechanical etiology of diabetic foot ulcerations. Am Pod Med Assoc 85:519±527 36. Bouten CVC, Knight MM, Lee DA, Bader DL (2001) Compressive deformation and damage of muscle cell sub-populations in a model system. Ann Biomed Eng 29:153±163 37. Bliss MR (1993) Aetiology of pressure sores. Rev Clinical Gerontol 3:379±397 38. Breuls RGM, Bouten CVC, Oomens CWJ, Bader DL, Baaijens FPT (2003) Compression induced cell damage in engineered muscle tissue: an in-vitro model to study pressure ulcer aetiology. Ann Biomed Eng 31:1357±1365 39. Bouten CVC, Oomens CWJ, Baaijens FPT, Bader DL (2003) The aetiology of pressure sores: skin deep or muscle bound? Arch Phys Med Rehab 84:616± 619

Medical Perspectives in the 21st Century Jeen Haalboom

2

Epidemiological Studies on Pressure Ulcers in The Netherlands Pressure ulcers occur regularly in clinical practice. In a recent Dutch prevalence study [1], in which more than 38,000 patients were examined, it was reported that approximately 13% of patients in university hospitals had pressure ulcers, 23% exhibited them in general hospitals, 30% in nursing homes and 17% in home care. This is unacceptably high, but similar figures have been found in studies from other countries. For example, in a smaller prevalence study in the UK, commissioned by the European Pressure Ulcer Advisory Panel (EPUAP) in 2001, 21.8% of all patients had established pressure ulcers. Comparable data were also obtained from studies in Canada [2] and in Europe (ongoing EPUAP study). It may be concluded that pressure ulcers occur much more regularly than would normally be presumed. Indeed, the figures are so alarming that more specific data are still needed and it is therefore necessary to work with frequency data. There are several sets of frequency data in use that illustrate the extent of `the problem' of pressure ulcers. In the Netherlands in the period 1998± 2001, annual prevalence recordings were performed, conducted by the Steering Committee on Pressure Ulcers. In particular, details were obtained related to prevalence. By contrast, there is a relative paucity of data regarding the incidence of pressure ulcers. Prevalence is defined as the number of patients with pressure ulcers at a certain moment, i.e. point recording, usually expressed as a percentage of the total number of patients admitted to an institution. The main goal of prevalence data is to obtain an insight into the magnitude of the problem of pressure ulcers and, to a lesser extent, the factors contributing to their development. Prevalence provides a reflection of the availability and/or efficiency of the labour of nursing personnel and the use of prevention and treatment protocols. There are large differences in prevalence data among institutions and countries. In large studies in hospitals, prevalence figures ranging from 5.2 to 18.6% have been reported [3±5], with equivalent ranges in nursing homes of between 7.9 and 33.2% [6±9], and in home-care situations of between 4.9 and 29.1% [10, 11]. However, prevalence figures as found in the literature are difficult to compare mainly due to diversity in methodology. Typical methods employed have been:

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1. Use of a questionnaire [5, 7, 10]. 2. Retrospective analysis of patient files [6, 12]. 3. Investigation of patients obviously at high risk of developing pressure ulcers [3, 4]. In addition, the use of different classification systems for pressure ulcers makes the comparison of prevalence figures very problematic. In some studies, pressure ulcers were recognized as a discolouration of the skin [13±15], in others when this discolouration was non-blancheable [16, 17] and in others when a skin defect was evident [17]. Prevalence recordings should be compared only when a distinctive internationally recognized classification system is established and regularly used [18]. The inclusion of stage 1 pressure ulcers, defined as non-blancheable discolouration of the skin, in the overall classification of pressure ulcers is an important explanation for the differences found in the literature for both prevalence and incidence between institutions and countries. In the Dutch prevalence studies 60±75% of the patients with pressure ulcers were considered to exhibit grade 1 ulcers. Thorough examination and documentation of patients is of critical importance, since somewhere within the domain of the so-called grade 1 pressure ulcer there is a turning point, the watershed between full recovery and the progressive development of more severe pressure ulcers. As far as the method of prevalence studies is concerned it is important that, without exception, all patients in an institution are examined. The three methods detailed above all underestimate the true prevalence. They suppose that all patients with pressure ulcers are known to the nursing staff or that every patient with pressure ulcers is registered in the nursing file. If the only patients examined are those with a perceived increase in risk of developing pressure ulcers, it is wrongly assumed that patients without such an increased risk all do not have pressure ulcers. Further analysis of the 1999 prevalence study in the Netherlands showed that out of all patients examined, 3112 had one or more pressure ulcers [1]. However, using the Braden risk assessment tool, 37% of these patients did not have an increased risk. It could be assumed that all patients with stage 3 and 4 ulcers should be known to the nursing staff. For patients with ulcers stages 1 and 2 this was not the case. Of the 37% of patients without an increased risk, no less than 61% demonstrated stage 1 lesions, 25% stage 2 and, more remarkably, 14% stages 3 and 4. Thus if only patients with an increased risk had been examined, these patients would have been missed and, accordingly, the prevalence figures would have been much lower. Until 1998 there was no insight into the scale of the problem of pressure ulcers in terms of intra- and extra-mural healthcare in the Netherlands. It was assumed that prevalence was 8±10% in hospitals and 15±20% in nursing homes [19]. In Table 2.1 the results of a Dutch prevalence study in the period 1998±2001 are presented, with respect to the type of institution and grade of pressure ulcer. The sample was considered to be representative for the whole population of healthcare institutions in the Netherlands. The first study

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Table 2.1. The results of a Dutch prevalence study in the period 1998±2001 Stage 1

Stage 2

Stage 3

Stage 4

Total

5.6 6.0 8.5 5.2

4.9 4.1 7.6 6.1

2.1 3.2 2.1 2.6

0.6 1.0 0.9 1.2

13.2 14.4 15.8 18.4

11.5 10.1 10.8 11.3

7.4 5.9 6.2 7.2

3.4 3.2 3.0 3.0

1.0 1.1 1.0 0.9

23.3 20.3 20.9 22.3

17.5 14.8 19.1 20.8

8.5 7.6 7.7 7.3

3.7 4.2 3.5 3.7

2.7 2.4 1.8 1.6

32.4 28.3 32.1 33.4

10.1 8.0 8.5 9.6

5.9 5.3 5.0 6.2

4.4 3.8 3.1 3.4

0.9 0.5 1.1 1.3

21.3 17.7 17.7 20.5

10.1 6.4 7.2 10.3

3.0 2.6 2.5 3.0

1.8 2.3 2.8 1.2

0.5 0.3 1.1 0.2

15.5 11.6 13.6 14.6

University hospitals 1998 1999 2000 2001 General hospitals 1998 1999 2000 2001 Nursing homes 1998 1999 2000 2001 Home care 1998 1999 2000 2001 Elderly care 1998 1999 2000 2001

showed that prevalence was much higher than was assumed, while studies in subsequent years did not reveal large changes, despite the introduction of a number of preventive measures. There is no obvious explanation for this finding, although it is possible that the increasing age of the patients with an associated increase in the severity of their illness might negate the possible positive effect of improved preventive measures. There are no large-scale prevalence studies known for intensive care situations. One study, however, revealed a prevalence of between 40 and 50% [20]. Incidence is defined as the number of new patients developing pressure ulcers in a defined period of time in relation to the total number of patients. As a rule, it is expressed as the number of patients presenting with pressure ulcers in a month or a year since admission. As with prevalence, there is no agreement about the criteria for incidence in the literature. The

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description of different patient populations and the use of different classifications and methods limit direct comparisons. Studies are most likely to represent so-called cumulative incidences, namely the number of new cases during the study divided by the total number of patients in the whole study. Here it is assumed that all patients participated in the study for the same period of time. In most studies, however, the admission times were not equal. Some patients died, some were discharged earlier, while other patients were admitted for prolonged periods. The use of the ªincidence rateº is the preferable solution in this respect, representing as it does the number of new cases during the study per number of days, months or years that the patients participated in the study. Incidence of pressure ulcers among hospital patients varies between 2.7% and 29.5% [21±25]. In several sub-populations even higher figures are reported. For example, in surgical patients incidence varies between 2.7% and 66% [26±33] and in intensive care patients between 5 and 50% [34± 38]. In homes for the elderly incidence values of between 2.4 and 77.3% have been estimated [21±23, 37, 39±41]. No incidence data have been reported for nursing homes. Recently in both the EPUAP and the Dutch Steering Committee on Pressure Ulcers there has been extensive debate about the comparative values of prevalence and incidence data. It was concluded that prevalence is of limited value, pointing towards the extent of the problem, without clarifying details of the factors that contribute to the development of pressure ulcers. In addition, the effects of preventive interventions are not measured using prevalence data and it is impossible to make comparisons between institutions (see Chap. 3). The tendency exists to use prevalence data to judge individual institutions, but the limitations of assessments such as the Braden risk assessment tool impart limited value to the data. A Canadian Table 2.2. Incidence study at the University Medical Centre Utrecht (n = 400) Gender

Number

Mean age

Men

186 (46.5%)

57.8Ô17.6

Women

214 (53.5%)

Pressure ulcers

47 (11.8%)

66.9Ô70

Surgical patients Number Pressure ulcers

234 32 (13.6%) Non-surgical patients

Number Pressure ulcers

166 15 (9%)

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study showed that in one institution prevalence can change considerably with time, for the most part at a constant incidence. In a prospective study in Utrecht University Hospital, part of the prePURSE study [39, 40], the value of incidence was again illustrated. In total 400 patients were analysed, 234 of whom were on surgical wards, and the remainder on wards for internal medicine and neurology. They were investigated three times weekly for a period coincident with their individual hospitalization or until the occurrence of a pressure ulcer. Results indicated that there were significantly more patients with pressure ulcers on the surgical wards (13.6 versus 9%). It was also shown that longer operations are associated with a higher incidence of pressure ulcers, with median values of 4.4 h and 2.9 h for pressure ulcer and non-pressure ulcer patients, respectively. In addition, the mean age of 66.9 years was significantly higher than the mean age of 57.8 years for the population as a whole. Figures 2.1 and 2.2 illustrate the age pattern of the patients on the surgical and non-surgical wards and the time of development of the pressure ulcers, respectively. It is striking that in surgical patients pressure ulcers do not occur exclusively in the elderly, but also in the younger age group, particularly the latter undergoing extensive head and neck surgery. Figure 2.2 also shows that pressure ulcers routinely can be observed in the second week of admission [39, 40]. This contradicts the long-held supposition that pressure ulcers were caused by inadequate nursing care; rather, it strongly suggests that many pressure ulcers develop during operation and/or periods of treatment in the emergency rooms or during investigations in, for example, X-ray departments where mattresses have not been routinely adapted to these severely ill patients. This explains the high incidence in head and neck patients, operated upon in a half-sitting position, who develop ulcers in the sacral region. It is noteworthy that adaptation to the operation table diminished the incidence sharply. This finding was reported in incidence, as opposed to prevalence, surveys. Pressure ulcer care should

Fig. 2.1. Incidence study. Surgical patients: age distribution in decades

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Fig. 2.2. Incidence study. University Medical Centre Utrecht: week of development of pressure ulcers

therefore also be focused on the situations in both hospital and community settings, during which patients are vulnerable to soft tissue breakdown.

Costs of Pressure Ulcer Care With a population of 16 million, the combined cost of the prevention and treatment of pressure ulcers in the Netherlands is approximately 1 600 million per year [42, 43]. The total amounts to more than 1% of the total national costs of healthcare. Thus pressure ulcers constitute an important financial burden on the Dutch health budget, behind only the management of cancer, AIDS and cardiovascular diseases. With equivalent levels of healthcare it is only logical that in other technically advanced countries comparable amounts of money are spent per capita. These enormous costs have attracted the increased attention of organizations managing healthcare, such as the Ministry of Health, as well as health insurance companies. When dealing with increasing costs more detailed studies involving the analysis of the generation of these costs is an important first step. It was concluded that there are distinct patterns distinguishable in pressure ulcer care, namely: 1. Prevention is cheaper than appropriate forms of treatment. 2. Costs are mainly generated by longer hospital admissions once an ulcer has become established in a patient. 3. Special devices are expensive. Therefore in the Netherlands, at least, attention is now more focused on prevention. Prevention implies that patients at risk should be routinely monitored and managed with appropriate prophylactic measures, whereas patients not at risk should not receive special attention. Thus identification of patients at risk is critical, although it remains questionable which methods should be used in this process. Current risk assessment tools are of only limited value. These tools can be examined with respect to their speci-

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ficity and sensitivity, using receiver operating characteristic (ROC) curves. Prospective studies revealed ROC curves indicating values of approximately 50%, comparable to the probability of correctly selecting the outcome when tossing a coin. Figure 2.3 shows the results of the prePURSE study involving 1,200 patients [39, 40], in which prospectively all factors of the established risk assessment instruments were recorded. The main conclusions were that surgery implied a certain risk, but that the predictive utility of the tools is, at best, limited. This finding is important, since in most institutions preventive interventions are taken, and in fact considered as good nursing practice, when a risk tool indicates increased risk. Using these instruments means that preventive measures may be adopted in patients who are not at risk but not employed in patients who really are at risk. Changing the threshold limits that define risk/no risk only provides a cosmetic solution. A complete revision of the factors associated with risk assessment is urgently needed. Since the Waterlow tool was primarily designed to assess surgical patients, its predictive performance was slightly better than the others tested (Fig. 2.3). Risk assessment tools were developed in nursing to improve clinical skills and to analyse what could be considered to be a clinical view. This personal expertise of well-trained nurses still has an impact. In the recent Dutch Guideline on Pressure Ulcers (2002) the use of risk assessment tools is still encouraged, but in combination with ªclinical viewº, since the combination of the two tends to identify patients better than not using either of them. It is likely that, in the near future, some more scientifically based tools will become available. However, such tools will need to accommodate the complex recent challenges associated with an ever-older population. These include more severely ill patients, many of whom are treated

Fig. 2.3. ROC curve, defining sensitivity and specificity of risk score lists (adapted from [39])

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as outpatients and who enjoy less home-care facilities. It is still uncertain whether these factors will lead to an increased risk and need to be treated as such. In additional to the marginal scientific evidence associated with risk assessment, there are few quality studies investigating the effects of nursing and medical interventions. Indeed, studies examining the effects of beds are so rare, that medical and nursing journals tend to publish studies without the normal scientific rigour. As an example, a so-called controlled study was published in the Lancet in 1994 [41], investigating the effects of removing some foam blocks from a mattress. At first glance the statistics appeared to suggest that the modified mattress performed better than the control standardized hospital mattress. On closer examination, however, neither had the characteristics of both devices been specified nor was there any questioning as to why on the standard mattress the incidence of pressure ulcers was 60% (with hip fractures), although in a normal setting the value would have been predicted to be 20%. With the new tested mattress the incidence was 23%. Better? Yes, better than the previously used standard mattress, but was it any improvement on other mattresses considered to be ªanti-pressure ulcer devicesº? In a recent study by the College for Health Insurances in the Netherlands, no less than 200 such mattresses were listed (CVZ, 2002). The Cochrane study group concluded in 2000 that there is no evidence that any special device is better in preventing and treating pressure ulcers than any other. They did, however, stipulate that foam mattresses must be at least 80 mm thick and stated that air-fluidized beds had a tendency to perform better in high- or intensive care patients. It is obvious that the manufacturer of the block mattress advertised very aggressively and made a lot of money from the publication of the study [41]. The first step in reducing overall costs to the providers should be limitation of the number of devices after an extensive objective evaluation of all the commercially available systems. Limitation of the number of devices should decrease the price of the individual item. Indeed, experimentation in some institutions with the replacement of all old hospital mattresses by mattresses known as anti-pressure ulcer mattresses has already demonstrated that the costs of pressure ulcer care can be decreased by more than 30% in one year. To conclude, pressure ulcers occur often and are even likely to increase in frequency in an ever-older population. Costs are largely generated by increased admission periods in institutions, and attention should be focused on the use of accurate and reliable prediction tools and well-tested preventive measures. Both the risk assessment instruments and the preventive materials need urgent testing, since their successful implementation could make a considerable impact on reducing the incidence of pressure ulcers.

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References 1. Meehan M (1990) Multi-site pressure ulcer prevalence survey. Decubitus 3:14±17 2. Davis CM, Caseby NG (2001) Prevalence and incidence studies of pressure ulcers in two long-term care facilities in Canada. Ostomy Wound Management 47:28±34 3. O'Dea K (1993) Prevalence of pressure damage in hospital patients in the UK J Wound Care 2:221±211 4. Barrois B, Allaert FA (1995) A survey of pressure sore prevalence in hospitals in the greater Paris region. J Wound Care 4:234±236 5. Zulkowski K (1999) MDS + Items not contained in the pressure ulcer RAP associated with pressure ulcer prevalence in newly institutionalized elderly. Ostomy/Wound Management 45:24±33 6. Shiels C, Roe B (1998) Pressure sore care. Elder Care 10:30±34 7. Weiler PG, Kecskes D (1990) Pressure sores in nursing home patients. Aging 2:267±275 8. Young L (1989) Pressure ulcer prevalence and associated patient characteristics in one long-term care facility. Decubitus 2:52±55 9. Inman C,Firth JR (1998) Pressure sore prevalence in the community. Professional Nurse 13:515±520 10. Oot-Giromini BA (1993) Pressure ulcer prevalence, incidence and associated risk factors in the community. Decubitus 6:24±32 11. Schue RMRM, Langemo DKRP (1998) Pressure ulcer prevalence and incidence and a modification of the Braden scale for a rehabilitation unit. JWOCN 25:36±43 12. Gruen RLS, et al (1997) Point prevalence of wounds in a teaching hospital. Aust N Z J Surg 67:686±688 13. Vandenbroecke H, et al. (1994). Decubitus in de thuis-verpleging. Het risico en de screening. Nationale Federatie van de Wit-Gele-Kruisvereniging, Brussels 14. Eckman KL (1989) The prevalence of dermal ulcers among persons in the U.S. who have died. Decubitus 2:36±40 15. Barczak CA, et al. (1997) Fourth national pressure ulcer prevalence survey. Advances in Wound Care 10:18±26 16. Berlowitz DR, et al. (1996) Rating long-term care facilities on pressure ulcer development: importance of case-mix adjustment. Ann Intern Med 124:557±563 17. Haalboom JRE, et al. (1997) Pressure sores: incidence, prevalence and classification. In Parish LC, Witkowski JA, Crissey JT (eds) The decubitus ulcer in clinical practice. Springer, Berlin Heidelberg New York, pp 12±23 18. Gunning-Schepers LJ, et al. (1993) Decubitus in Nederland. Een onderzoek naar de mogelijkheden om het voorkomen van Decubitus in Nederland te meten. Instituut voor Sociale Geneeskunde, Universiteit van Amsterdam, Amsterdam 19. Bours G, Halfens R (1999) Decubitus komt nog veel te veel voor. TVZ 20:608±611 20. Xakellis GC, Frantz RA, Lewis A, Harvey P (1998) Cost-effectiveness of an intensive pressure ulcer prevention protocol in long term care. Adv Wound Care 11:22±29 21. Severens J (1999) Kosten van decubitus in Nederland. Afdeling MTA, Universitair Medisch Centrum St. Radboud, Nijmegen

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22. Panel for the Prediction and Prevention of Pressure Ulcers in Adults (1992) Pressure ulcers in adults: prediction and prevention. Clinical practice guideline. Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services, Rockville. AHCPR Publication No. 92-0047 23. Goodridge DM, Sloan JA, LeDoyen YM, McKenzie JA, Knight WE, Gayari M (1998) Risk-assessment scores, prevention strategies, and the incidence of pressure ulcers among the elderly in four Canadian health-care facilities. Can J Nurs Res 98:23±44 24. Bergstrom N, Braden B, Kemp M, Champagne M, Ruby E. (1996) Multi-site study of incidence of pressure ulcers and the relationship between risk level, demographic characteristics, diagnoses, and prescription of preventive interventions. J Am Geriatr Soc 44:22±30 25. Allman RM, Goode PS, Patrick MM, Burst N, Bartolucci AA (1995) Pressure ulcer risk factors among hospitalised patients with activity limitation. JAMA 273:865±870 26. Clark M, Watts S (1994) The incidence of pressure sores within a National Health Service Trust hospital during 1991. J Adv Nurs 20:33±36 27. Grous CA, Reilly NJ, Gift AG (1997) Skin integrity in patients undergoing prolonged operations. J Wound Ostomy Continence Nurs 24:86±91 28. Hoyman K, Gruber N (1992) A case study of interdepartmental cooperation: operating room-acquired pressure ulcers. J Nurs Care Qual [Suppl]:12±17 29. Kemp MG, Keithley JK, Smith DW, Morreale B (1990) Factors that contribute to pressure sores in surgical patients. Res Nurs Health 13:293±301 30. Schoonhoven L (1998) Incidentie van decubitus op de operatietafel. 1-66. Internal report, Utrecht University 31. Baudoin C, Fardellone P, Bean K, Ostertag EA, Hervy F (1996) Clinical outcomes and mortality after hip fracture: a 2-year follow-up study. Bone 18:149S±157S 32. Bertelink BP, Stapert JW, Vierhout PA (1993) The dynamic hip screw in medial fractures of the femoral neck: results in 51 patients. Ned Tijdschr Geneesk 137:81±85 33. Stordeur S, Laurent S, D'Hoore W (1998) The importance of repeated risk assessment for pressure sores in cardiovascular surgery. J Cardiovasc Surg Torino 39:343±349 34. Thomas TA, et al. (1999) An analysis of limb-threatening lower extremity wound complications after 1090 consecutive coronary artery bypass procedures. Vasc Med 4:83±88 35. Keller P, Wille J, Ramshorst B van, Werken C van der (2002) Pressure ulcers in intensive care patients: a review of risks and prevention. Intensive Care Med 28(10):1379±1388 36. O'Sullivan KL, Engrav LH, Maier RV, Pilcher SL, Isik FF, Copass MK (1997) Pressure sores in the acute trauma patient: incidence and causes. J Trauma 42:276±278 37. Olson B, Langemo D, Burd C, Hanson D, Hunter S, Cathcart ST (1996) Pressure ulcer incidence in an acute care setting. J Wound Ostomy Continence Nurs 23:15±22 38. Langemo DK, Olson B, Hunter S, Hanson D, Burd C, Cathcart ST (1991) Incidence and prediction of pressure ulcers in five patient care settings. Decubitus 4:25±30

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39. Schoonhoven L, Haalboom JRE, Bousema MT (2002) Prospective cohort study of routine use of risk assessment scales for prediction of pressure ulcers. BMJ 325:797±799 40. Schoonhoven L (2003) Prediction of pressure ulcers: problems and prospects. PhD thesis, University of Utrecht, ISBN 90-393-3264-9 41. Hofman A, Geelkerken RH, Wille J, Hamming JJ, Hermans J, Breslau PJ (1994) Pressure sores and pressure decreasing mattresses: a controlled clinical trial. Lancet 343:568±571

Medico-Legal Implications Courtney Lyder

3

Introduction The medico-legal implications of pressure ulcer development are burgeoning throughout the world. Increasingly, pressure ulcers are being used as a quality indicator of care. Hence, the development of pressure ulcers can constitute a failure in the healthcare system. In the United States, the federal government believes that pressure ulcers are an excellent surrogate for how well the healthcare team is functioning. Thus, a high incidence of pressure ulcers usually can be correlated with high incidence of other care issues (e.g. falls, restraint usage, urinary incontinence). One aspect of the increasing view of pressure ulcer development as a marker for quality care has been the increasing level of pressure ulcer litigation against clinicians and their employers (hospitals, nursing homes, etc.). This chapter will review various aspects of the medico-legal implications of pressure ulcer development. More specifically, it will review pressure ulcers as a political agenda; the legality of pressure ulcers; regulatory and reimbursement aspects of pressure ulcers; necessity of chart audits related to pressure ulcers; and pressure ulcers as a quality measure.

The Politics of Pressure Ulcers In the past 10 years, there has been a fundamental paradigm shift in how governments and consumers of healthcare have thought about pressure ulcer development. In part, this has occurred because of a greater need of governments to control burgeoning healthcare costs associated with an ever-increasing older adult population. Although the true cost associated with pressure ulcer prevention and development remains unknown, these ulcers can significantly increase healthcare expenditures. For example, in the Netherlands pressure ulcer treatment is conservatively estimated from a low of $ 362 million to a high of $ 2.8 billion, 1% of the total Dutch healthcare budget [1]. In the UK, the costs of pressure ulcers have ranged annually from £ 180 million to £ 321 million, or 0.4±0.8% of healthcare spending [2] (see Chap. 2). The financial costs to the National Health Service (NHS) are also substantial. Preventing and treating pressure ulcers in a 600-bed general hospital costs between £ 600,000 and £ 3 million a year,

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excluding litigation costs [3]. In the United States, it has been conservatively estimated that the treatment cost alone ranges anywhere between $ 1.68 billion to $ 6.8 billion or more than 1% of the total U.S. healthcare budget [4]. These estimates do not account for pain, suffering, or potential days of lost income. Thus, pressure ulcers are an expensive health problem. The increasing accountability of healthcare clinicians to prevent and manage these wounds more effectively has led to an explosion of national guidelines on pressure ulcer. These national guidelines on prevention and treatment were developed by various healthcare providers and organizations as a method of streamlining and providing consistent pressure ulcer care. The earliest national guidelines were derived from the Netherlands and the United States [5]. Moreover, several governments have established national centres which have addressed quality pressure ulcer care. In the UK, the National Institute for Clinical Excellence released national guidelines on pressure ulcer risk management and prevention [6]. These guidelines were in part derived from the Royal College of Nursing. The NICE guidelines provide both a clinician and patient versions. The NICE guidelines are quite similar to the guidelines of the U.S. Agency for Health Care Policy and Research (now the U.S. Agency for Health Care and Quality) for pressure ulcer prevention in that both clinician and patient versions exist [4, 7]. Coupled with the growing needs for governments to manage their health expenditures more effectively, healthcare consumers have become increasingly aware through the media (internet, television) that pressure ulcers can be prevented and effectively treated. Thus, a more informed general public has led to the increasing need for healthcare providers to be educated on proper pressure ulcer care. One potentially negative consequence of an informed general public has been the increased scrutiny by the legal and/or government body to litigate or sanction penalties when care is not optimized.

Litigation There remains a steady increase in litigation related to either the development of pressure ulcers or failure to effectively manage them. This is fuelled by ever-increasing media attention to patients suffering from these ulcers. Moreover, in recent years there has been an effort by professional health organizations and ministries of health to educate the consumer on pressure ulcers. Although most cases may be settled through an inquiry by a health trust, there appears to be an increase of consumers seeking financial remedies. A growing number of health professionals view the development of pressure ulcers as evidence of negligent care by a healthcare provider or health system. In one study by Tsokos et al. [8], 11.2% of 10,222 corpses in Germany were found to have a pressure ulcer. This study found that the ma-

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jority of physicians did not associate the potential fatal outcome of pressure ulcers and fatalities (e.g. sepsis) related to the development of these ulcers. Moreover, the investigators stated that the prevalence of pressure ulcers is a good parameter of quality nursing and medical care, thus the field of legal medicine can contribute significantly to general quality control of standards of nursing and medical care. The assumption that pressure ulcers result from poor care by the medical and/or nursing staff has led to a flood of litigation. These lawsuits often lead to significant financial outlays by healthcare providers and/or healthcare institutions. In a retrospective study investigating the lawsuit judgment in cases of patients developing pressure ulcers on admission to hospitals, it was found that a significant number of medico-legal cases of pressure ulcer development could easily have been avoided at little expense to the healthcare institution. Thus, if the healthcare institution had provided systematic and comprehensive preventative measures it could have potentially avoided many lawsuits. The investigators found that the damages awarded varied from £ 3,500 to £ 12,500, although there have been cases with damages in excess of £ 100,000 [9]. In the U.S. pressure ulcer litigation has become rampant. In fact, it has become common for plaintiff attorneys to advertise on televisions and newspapers; they have even begun to advertise on roadside billboards. In a study investigating typical pressure ulcer awards in the U.S., sums ranging from $ 5,000 to $ 82,000,000, with a median award of approximately $ 250,000, have been reported [10]. Most revealing in this study was that the average age of the plaintiff was 72 years. This indicates that an increasing number of older adults are bringing legal cases against healthcare providers and health institutions. The following case study highlights elements of how healthcare providers and healthcare institutions can be easily exposed to litigation. ª83 y.o. male was admitted to hospital with history of congestive heart failure, right cerebral vascular accident, early stage dementia, urinary and faecal incontinence. A pressure ulcer risk assessment scale was completed indicating that the patient was at mild risk for pressure ulcers. The patient was placed on a standard mattress with a 4 inch solid foam overlay, turned every two hours while in bed and chair. On Day 2 of hospital admission, a nurse indicated an ªerythematicº area on left hip and heel. She intervened by gently massaging the two erythematic areas with lotion and turned the patient on the right side. By Day 5, a Stage 2 pressure ulcer was noted on the left hip and a Stage 1 pressure ulcer was noted on the left heel. A hydrocolloid dressing was placed on the Stage II pressure ulcer, and nothing was ordered for the Stage I pressure ulcer. The charts noted that a tissue viability nurse would be consulted. By Day 8, a Stage III pressure ulcer was noted on left hip and heels. The Tissue Viability Nurse changed all of the wound care ordersº. This case highlights some common errors made by the hospital staff. To identify a couple of areas of concern, the patient was at extreme high risk for pressure ulcers since he had multiple health conditions that rendered him immobile (congestive heart failure, right cerebral vascular accident,

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early stage dementia, urinary and faecal incontinence). Moreover, the risk assessment tool showed only mild risk. This is an important factor, indicating that the tool may have been completed incorrectly. Further, no pressure ulcer risk assessment tool has 100% sensitivity and specificity [11] (see Chap. 2). The patient was only placed on a standard mattress with a foam overlay. Given the patient's risk level, a dynamic surface (alternating air mattress, etc.) might have been more appropriate. Further complicating this patient's condition was the massaging of the erythematic area on the patient's left hip and heel. Research indicates that massaging a red spot may actually deepen the devitalized area [12]. Further, although a hydrocolloid dressing was ordered for the stage 2 pressure ulcer, nothing was ordered for the stage 1 ulcer (e.g. removing load from the heel). In this case study, it was obvious that additional preventive measures were not instituted; thus these pressure ulcers could perhaps have been avoided. The above case scenario could occur anywhere in the world. Thus, any healthcare provider could be exposed to litigation when caring for a patient with a pressure ulcer. It appears that several key factors must be met to bring a pressure ulcer case to court. Most cases involve negligence; in other words, the healthcare professional and/or healthcare institution failed in providing care. There are three major factors that must be fulfilled to prove negligence. These three factors are accountability, causation and breach of standard of care [13]. When all three are met, the verdict will be for the plaintiff. The first key factor is accountability. Hence, the plaintiff was owed a duty of care, and this duty of care was breached. Moreover, the breach of care resulted in permanent damage or injury, and the plaintiff is owed compensation due to the injury. This factor is easily acknowledged since any patient that enters a hospital, nursing home or home care setting is owed a certain level of care by healthcare providers. Since pressure ulcers can develop when preventive measures are not implemented, it is very easy to meet this standard. The second factor is causation. Thus, the harm suffered by the patient was a foreseeable consequence of the breach of the duty of care. Although the majority of patients that develop pressure ulcers do not die due to the pressure ulcer, pressure ulcers (especially stage 3 and 4 ulcers) can increase the potential for infections (sepsis, cellulites). Pressure ulcers may also be quite painful. Proving causation can be quite easy, especially when the medical record is void of good documentation of the type and quality of care provided. The absence of good documentation on the preventative services provided or treatments carried out can make it easy for a plaintiff attorney to show that lack of care caused the formation of the pressure ulcer. The final factor is the standard of care by staff. It is important to note that the standard of care is not at the level of an expert, but rather that of an average healthcare professional. Most often, expert practitioners are used to determine the expected skill mix of the average healthcare provider related to wound care. A physician expert would be used to determine the physician skill mix and a nurse expert would be used to determine a nurse

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skill mix. When the expert resides in a country that has developed national guidelines on the prevention and treatment of pressure ulcers, quite often these will be used to determine the appropriateness of pressure ulcer care. One study investigating the impact of implementation and subsequent compliance with practice guidelines in mitigating exposure to litigation found that of 49 plaintiff cases with compensations worth $ 14,418,770, use of guidelines could have saved the defendant $ 11,389,989 [14]. It appears that national guideline recommendations can be costly to implement for many healthcare institutions. One study found that the cost of implementing support surface equipment varies widely, from over £ 30,000 for some bed replacements to less than £ 100 for some foam overlays [15]. According to the UK National Health Service many clinical areas will already have access to equipment, but this is not always the case ± especially for the pressure-redistributing overlays/mattresses on operating tables, which are supported by relatively recent and convincing evidence for use in high-risk individuals. Local decisions need to be made about the access and purchase of equipment in the light of available resources [15]. Consideration also needs to be given to the ongoing costs of equipment maintenance and replacement, given that the average daily cost of managing a pressure ulcer ranges from £ 38 to £ 196 with little variation by stage of ulcer [16].

Documentation One major factor in decreasing the exposure to litigation appears to be the adequacy of documentation. Comprehensive documentation is also requisite for reimbursement of services and products in some countries. Moreover, good documentation justifies the medical necessity of services and products. Regulatory agencies, independent of healthcare setting, provide requisite documentation to justify continuation of pressure ulcer care. Good documentation should reflect the care required in the prevention and/or treatment of pressure ulcers [17]. Essential documentation should include the following, independent of healthcare setting:

Prevention of Pressure Ulcers 1. 2. 3. 4.

Risk assessment tool (e.g., Waterlow, Norton, Braden tools) Daily skin assessment Repositioning (off loading) and turning schedules Use of support surfaces to address pressure redistribution (both bed and chair) 5. Control of moisture from perspiration and urinary and faecal incontinence 6. Nutritional assessment and supplementation when appropriate 7. Education of patient and/or family

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Treatment of Pressure Ulcers 1. Regular assessment/reassessment of the wound (daily, weekly, etc.) 2. Characteristics of the ulcer a) length b) width c) depth d) exudate amount e) tissue type f) pain 3. Local wound care 4. Wound-bed preparation 5. Repositioning (off loading) and turning schedules 6. Use of support surfaces to address pressure redistribution (both bed and chair) 7. Control of moisture control from perspiration and urinary and faecal incontinence 8. Nutritional assessment and supplementation when appropriate 9. Use of adjunctive therapies (negative-pressure wound therapy, electrical stimulation, etc.) 10. Education of patient and/or family

Regulation and Reimbursement It is universally accepted that patients receiving care in hospitals, nursing homes or the community should be free of pressure ulcers or, if ulcers exist, care should be provided to treat them effectively. The majority of healthcare settings are under the auspices of the national ministry of health, which has broad parameters for operating the various trusts (usually determined by geographical locations) within a specified country. With the socialized healthcare still prevalent in European and South American countries, quality pressure ulcer care is most dependent on the resource allocation by the specific healthcare trust. To this end, the quality of pressure ulcer care (as measured by support surfaces, types of dressings, adjunctive therapies used) may vary greatly dependent on the trust. The Canadian and Mexican models for pressure ulcer care are quite similar to the European model. Thus, pressure ulcer regulation and resource allocation for the acquisition of dressings, support surfaces, and adjunctive therapies (e.g. negative-pressure wound therapy) are dependent on the provincial trusts. In these systems, one trust may provide superior wound care based on the amount of resources that are allocated to pressure ulcer care. It should be noted that complaints by a health consumer or family are usually addressed by the individual trusts. Probably the most regulated country with regard to pressure ulcer care is the United States. With the federal government being the largest health

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insurer (through Medicare), regulations exist for all settings related to reimbursement and survey process for ensuring quality pressure ulcer care. Although a given state may have additional regulations, all states must follow the federal regulations. For example, in nursing homes, the quality for pressure ulcers is ensured by the federal survey process guidelines [18]. These guidelines state that: 1. A resident who enters the facility without a pressure ulcer does not develop pressure ulcers unless the individual's clinical condition is such that they were demonstrably unavoidable. 2. A resident having pressure ulcers receives necessary treatment and services to promote healing, prevent infection and prevent new ulcers from developing. Federal and/or state surveyors visit all 19,000 nursing homes in the U.S. to ensure compliance with the federal mandate. The inspections are unannounced and may occur at any time of the day (10% of visits must occur in the evening or night time). To assist the surveyors in evaluating whether a nursing home is compliant with the federal mandate, an investigative protocol is followed that covers all areas of pressure ulcer care (assessments, prevention, documentation, treatment, etc.). If the nursing home has been found to be non-compliant, then monetary penalties are calculated based on the seriousness of the violation. The maximum penalty for non-compliance is $ 10,000 per day [18]. If the violation is serious enough, the nursing home can be closed immediately. For example, if a survey team finds more than one resident with Stage 3 or 4 ulcers that they believe were avoidable, then the nursing home can lose all financial support from the federal and/or state governments. Some have argued that the survey team only has to prove that the pressure ulcer developed after admission to the nursing home, whereas the nursing home must prove that the pressure ulcer was unavoidable [19]. Given that all aspects of care are usually not documented, proving unavoidability is difficult. It should be noted that all nursing home survey results are in the public domain and can be accessed on the government website. This places more pressure on nursing homes to reduce their pressure ulcer rates, since it may affect the decision by families to place their loved ones in a particular home. In an attempt to understand the magnitude of adverse events in U.S. hospitals, the federal government has developed a monitoring program to track multiple patient safety issues. One of the first clinical indicators under study is pressure ulcers. In this program, the development of pressure ulcers in a hospital could be classified as a medical error. Presently, the data are being collected; however, this initiative will have potentially significant regulatory and legal implications for U.S. hospitals. Until December 2002, Japan used the universal health coverage paradigm, similar to Europe and Canada. However, in January 2003 Japan introduced a modified prospective payment system on a select group of health conditions for hospitalized patients [20]. The new system is consid-

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ered a hybrid between the European universal coverage and the American prospective payment system. Pressure ulcers were selected as one of the health conditions to be pilot tested. Hospitals will need to begin to track pressure ulcer incidence and outcomes of interventions. Moreover, hospitals are now required to have an interdisciplinary wound team (comprising at least physicians and nurses). All patients with pressure ulcers must be evaluated and a plan of care instituted. Although the defined acceptable rate of pressure ulcers has not been released, hospitals exceeding this incidence rate will incur monetary penalties [20].

Benchmarking The ability to benchmark incidence or prevalence rates for any disease condition is critical to assess the health status from a national, regional, local or institutional level. Without obtaining incidence or prevalence data, it is difficult to ascertain the effectiveness of preventative or treatment interventions (also see chapter 2). Thus, chart audits have become extremely popular throughout the world. In the past 10 years, numerous studies have published incidence and prevalence data on pressure ulcers. Both measure disease frequency. Incidence measures the proportion of people at risk for the disease (pressure ulcer) who eventually acquire the disease (pressure ulcer) over a specific period of time [21]; it conveys the likelihood that an individual in that population will be affected by the condition. Prevalence is the proportion of people who have the disease (pressure ulcer) in a specified population at risk [22, 23]. Studies usually report point prevalence, which is the prevalence rate for a specific point in time (what is the prevalence of pressure ulcers for today?). Period prevalence refers to a prevalence rate over a given time (what is the prevalence of pressure ulcers over a 3-month period?) [24]. The National Pressure Ulcer Advisory Panel has published a comprehensive monograph on the prevalence and incidence of pressure ulcers in the U.S. This document also presents step-by-step guidance on how to conduct studies on both incidence and prevalence of pressure ulcers [25]. The prevalence and incidence rates appear to differ greatly depending on the healthcare setting studied and within countries. In Canada, researchers noted a point prevalence rate of 25.7% for pressure ulcers in hospital, nursing home and community care settings [26], while in Japan a point prevalence rate of 6% is common in hospital and nursing homes [27]. In the United Kingdom, point prevalence rates have ranged from 8.5 to 32.1% for hospitals and 2.5 to 6.1% in the community [28±30]. A study investigating period prevalence of pressure ulcers in 11 German hospitals found a range of 12±53.5%, with an average of 28.3% [31]. In the United States more studies exist that report the incidence of pressure ulcers. In attempting to understand whether or not there has been an overall decrease in the incidence of pressure ulcers in the United States, the

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National Pressure Ulcer Advisory Panel collected data from the published research literature over a 10-year period (1990 to 2000). They found incidence rates of 0.4±38% for hospitals, 2.2±23.9% for nursing homes and 0± 17% for home care [25]. When benchmarking published data on either incidence or prevalence of pressure ulcer it is imperative to ensure that you are comparing similar data points as well as patient or unit populations. For example, an incidence rate of 20% for a hospital may be significant or not, depending on what particular medical units were involved. If this information is not available, comparisons among hospitals, nursing homes, etc. will be very difficult to make and should be avoided.

Pressure Ulcers as a Quality Measure There has been little discourse on whether or not pressure ulcers should be used as an indicator of quality care. In fact, some have noted that the development of pressure ulcers results from a breakdown in the institutional system of care delivery because the prevention of pressure ulcers requires the cooperation and skill of the entire medical team. There is abundant literature that suggests that a large proportion of pressure ulcers can be prevented through systematic risk factor identification, skin assessments, use of effective support surfaces, and education of patients and staff. Implementation of a pressure ulcer prevention program is effective in decreasing the incidence of pressure ulcers in hospitals. However, few studies have been published that demonstrate the implementation prevention guidelines in their entirety, which is most likely due to the complex and interdisciplinary nature of pressure ulcer prevention. Several studies have reported the implementation of components of recommendations from the AHCPR guidelines. Gunningberg et al. [32], investigating the incidence of pressure ulcers in 1997 and 1999 among patients with hip fractures, attributed the significant reduction in incidence (from 55% in 1997 to 29% in 1999) to performance of systematic risk assessment on admission, accurate staging of pressure ulcers, use of pressure-reducing mattresses, and continuing education of staff. Another study, involving implementation of a comprehensive prevention program consisting of a risk assessment tool, uniform skin care, pressure-reducing support surfaces, repositioning schedules, standardized nutritional assessment and support, and staff education, found significant reductions in pressure ulcer incidence during a 5-month period [33]. Similar results have been noted elsewhere [34, 35]. Although these studies support the benefit of a comprehensive approach, no study could be found that has implemented all recommendations of the AHCPR prevention guidelines or any other national guidelines. Moreover, the sustainability of pressure ulcer reductions has not been studied for long periods. Pressure ulcers may indicate a potential problem within the healthcare organization, but some ulcers may be unavoidable. There is a paucity of lit-

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erature that suggests an acceptable rate for pressure ulcer development. Lyder suggested that a rate of 5% should be allowed, since not all risk factors have been identified nor has any study been published that consistently implemented a respective country's pressure ulcer prevention guidelines [11]. The discourse on avoidability versus unavoidability remains heated; however, little guidance can be found in the world literature beyond the assumption that the pressure ulcer may be deemed unavoidable if all preventative guidelines have been implemented and the ulcers develops.

Conclusion There remain numerous medico-legal issues related to pressure ulcers. Given the burgeoning world of electronic information technology, cutting-edge information on pressure ulcer care can readily be transmitted throughout the world. The ever-increasing knowledge level of the general public, primarily conveyed by the mass media, will most likely lead to increasing legal claims against healthcare providers and healthcare institutions. Healthcare providers will need to educate themselves on currently acceptable practices related to pressure ulcer prevention and treatment. This will also lead to more accountability within the healthcare community and in turn to increased documentation of care provided. The key to providing optimum pressure ulcer care will be good documentation that clearly articulates the needs for services and products implemented. Moreover, good documentation will clearly identify assessment of the patient, interventions instituted and outcomes achieved. As governments continue to quantify health expenditures related to pressure ulcers, there will be increased pressure on healthcare systems to address this costly problem. Many experts believe that the healthcare team has some capacity to thwart the development of pressure ulcers. Therefore, many countries may experience increased regulations related to pressure ulcer care, as already seen in Japan and the United States.

References 1. Severens JL, Habraken JM, Duivenvoorden S, Frederiks CM (2002) The cost of illness of pressure ulcers in the Netherlands. Adv Skin Wound Care 15:72± 77 2. Touche R (1993) The cost of pressure sores. Reports to the Department of Health. Department of Health, London, UK 3. http://www.nice.org.uk/pdf/clinicalguidelinepressuresoreguidancercn.pdf 4. Panel for the Prediction and Prevention of Pressure Ulcers in Adults (1992) Pressure ulcers in adults, prediction and prevention: Clinical practice guideline. Public Health Services Agency for Health Care Policy and Research, Rockville, MD, publication 92-0047. United States Census Bureau Statistics, Washington DC

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5. http://www.epuap.org 6. http://www.nice.org.uk/page.aspx?o=94726 7. U.S. Department of Health and Human Services (1994) Healthy People 2010 (conference edition in two volumes). Washington, DC: January 2000 8. Tsokos M, Heinemann A, Puschel K (2000) Pressure sores: epidemiology, medico-legal implications and forensic argumentation concerning causality. Int J Legal Med 113:283±287 9. Franks PJ (2001) Health economics: The cost to nations. In: Morrison MJ (ed) The prevention and treatment of pressure ulcers. Mosby, St Louis, pp 52±53 10. Bennett RG, O'Sullivan J, DeVito EM, Remsberg R (2000) The increasing medical malpractice risk related to pressure ulcers in the United States. J Am Geriatr Soc 48:73±81 11. Lyder C (2003) Exploring pressure ulcer prevention and management. JAMA 289:223±226 12. Lyder C (2002) Pressure ulcer prevention and management. Annu Rev Nurs Res 20:35±61 13. Dimond B (1999) Pressure ulcers and litigation. Nursing Times 99:61±63 14. Goebel RH, Goebel MR (1999) Clinical practice guidelines for pressure ulcer prevention can prevent malpractice lawsuits in older patients. JWOCN 26:175±184 15. www.guideline.gov/summary.aspx?ss=15&doc_id=2953&nbr=2179 16. Bennett G, Dealey C, Posnett J (2004) The cost of pressure ulcers in the UK. Age Aging 33:230±235 17. Lyder C (2003) Regulation and wound care. In Baranoski S, Ayello E (eds). Wound care essentials: practice principles. Springhouse, Springhouse, pp 35±46 18. Health Care Financing Administration: Investigative Protocol (2000) Guidance to surveyors ± long term care facilities. Rev 274. U.S. Department of Health and Human Services 19. http://www.nurses.info/law_for_nurses_journals.htm 20. http://www.mhlw.go.jp/english/ 21. Hulley S, Cummings S (1988) Designing clinical research: an epidemiologic approach. Williams and Wilkins, Baltimore, MD 22. Baumgarten M (1998) Designing prevalence and incidence studies. Adv Wound Care 11:28 23. Berquist S, Frantz R (1999) Pressure ulcers in community-based older adults receiving home health care. Prevalence, incidence, and associated risk factors. Adv Wound Care 112:339±351 24. Hennekens CH, Burling JE (1987) Epidemiology in medicine. Little Brown, Boston, MA 25. Cuddigan J, Ayello EA, Sussman C, Baranoski S (Eds) (2001) Pressure ulcers in America: prevalence, incidence, and implications for the future. National Pressure Ulcer Advisory Panel, Reston, VA 26. Foster C, Frisch S, Denis N, Forler Y, Jago M (1992) Prevalence of pressure ulcers in Canadian institutions. CAET J 11(2):23±31 27. Mino Y (2001) Pressure ulcers in bedridden elderly subjects. Jpn J Geriatrics 39:253±256 28. Torrance C, Maylor M (1999) Pressure sore survey: part one. J Wound Care 8:27±30 29. Allcock N, Wharrad H, Nicolson A (1994) Interpretation of pressure-sore prevalence. J Adv Nurs 20:37±45

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30. Hallett A (1996) Managing pressure sores in the community. J Wound Care 5:105±107 31. Gunningberg L, Lindholm C, Carlsson M, Sjoden P (2001) Risk, prevention and treatment of pressure ulcers ± nursing staff knowledge and documentation. Scand J Caring Sciences 15:257±263 32. Lyder C, Shannon R, Empleo-Frazier O, McGee D, White C (2002) A comprehensive program to prevent pressure ulcers: exploring cost and outcomes. Ostomy/Wound Management 48:52±62 33. Xakellis GC, Frantz RA (1996) The cost-effectiveness of interventions for preventing pressure ulcers. J Am Board Fam Pract 9:79±85 34. Regan MB, Byers PH, Mayrovitz HN (1995) Efficacy of a comprehensive pressure ulcer prevention program in an extended care facility. Adv Wound Care 8:51±52

Patients at Risk for Pressure Ulcers and Evidence-Based Care for Pressure Ulcer Prevention

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Nancy Bergstrom

Populations at Risk Pressure ulcers are a common problem in most healthcare settings. The elderly, those with spinal cord injury or other neurological deficits or degenerative processes, trauma patients, and those with any condition that limits the ability to move freely in response to the perception of discomfort are at risk for pressure ulcers. Newly recognized is the development of pressure ulcers as an end-of-life issue. The incidence of pressure ulcers is somewhat difficult to determine since there is no national registry of ulcers and many ulcers may remain unreported [1]. The incidence, projected from compiling reports of the incidence of pressure ulcers reported in research studies, is believed to be from 0.4 to 38% for hospitalized patients; 2.2 to 23.9% for long-term care; and as high as 17% in home care [2, 3]. The cost of pressure ulcers must be tabulated with consideration for costs of treatment, costs to the patient and the family, and the costs to society that are influenced by loss of time from work, costs of litigation and medical malpractice and more. Cost calculations to date are imprecise and tend to focus only on the cost of care, but several quality reports demonstrate that it costs less to prevent pressure ulcers than to treat them.

Specific Risk Factors Prolonged pressure caused by the weight of the body on muscle and skin over the bony prominences results in occlusion of blood vessels providing nutrients to the tissue, resulting in tissue death and necrosis. The amount and duration of pressure that can be tolerated without pressure ulcers has been studied in laboratory animals and humans, with a parabolic relationship demonstrated between the amount of pressure and the duration of exposure to pressure, with low pressure tolerated over longer intervals and high pressure tolerated over much shorter times [4±6]. Another early study demonstrated that there are different tissue injury thresholds for muscle and for skin, with muscle being more sensitive to the effects of pressure [7]. The precise amount of pressure necessary for pressure ulcer formation is variable and is likely to be influenced by the integrity of the tissue to which pressure is being applied.

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The list of factors associated with pressure ulcer risk is long, numbering more than 100, and includes medical diagnoses, co-morbidities and previous medical events (e.g. fractured hip, spinal cord injury, cerebrovascular accident, diabetes, previous pressure ulcer, cardiovascular disease, cancer, amputation) [8±10]; patient demographic characteristics (e.g. age, sex, race, marital status, socioeconomic status); anthropometric characteristics (e.g. height and weight, body mass index, triceps skin fold thickness, percent weight loss); physiological status (e.g. blood pressure, body temperature, glucose levels and control, tissue perfusion); nutritional status (e.g. serum albumin or pre-albumin, poor dietary intake); functional status (e.g. inability to control bladder and bowel function [11], number of deficits in activities of daily living, ability to feed self, activity and mobility levels); cognition (e.g. mental status, levels of consciousness) [12]; psychological status (e.g. stress, depression); social behaviour (e.g. substance abuse including drugs, smoking and alcohol); knowledge and adherence (e.g. educational level, knowledge of care requirements); and nursing care or facility characteristics (available RN and nursing assistant time, size or location of facility) [13], and more. Braden and Bergstrom [14] developed a conceptual scheme, based on a review of the literature, to create a framework for organizing risk factors (see Fig. 4.1). The conceptualization suggests that there are two major factors associated with pressure ulcer risk: the amount and duration of exposure to pressure and the ability of the tissue to tolerate the pressure. In the

Fig. 4.1. A conceptual scheme for the study of the aetiology of pressure sores which demonstrates linkages between key pressure ulcer risk factors (duration and intensity of pressure) and other risk factors [adapted from 14]

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clinical situation, pressure is influenced by mobility, activity and sensory perception. Mobility refers to the ability to turn and move about in bed. Persons who have a spinal cord injury, a fractured hip or are unconscious will not be able to move about and relieve pressure; thus, without assistance the time of exposure to pressure is increased. Activity refers to the ability to get out of bed, removing all pressure from non-weight-bearing surfaces (e.g. during ambulation) or shifting weight bearing to different pressure points (ischial tuberosities) during sitting. Sensory perception is the sum of the ability to perceive and the ability to act upon sensory information based on exposure to pressure. Individuals with a spinal cord injury, nerve damage, or a stroke may be insensate in specific body areas and be unable to detect discomfort associated with hypoxemia of local tissues exposed to pressure. Other individuals may be unable to appreciate or communicate discomfort associated with pressure due to dementia or other factors. Tissue tolerance for pressure is defined as the ability to withstand the effects of pressure without developing a pressure ulcer. Tissue tolerance may be influenced by intrinsic and extrinsic factors. Intrinsic factors occur within the individual, while extrinsic factors impinge on or cause deterioration of the external layers of the skin. Extrinsic factors most frequently include exposure to moisture from urinary or faecal incontinence, perspiration or other drainage resulting in maceration of the skin. One of the most frequently reported risk factors across many epidemiological studies of risk factors is urinary and/or faecal incontinence. Exposure to friction and shear also disrupts the skin. Studies have shown that persons subjected to friction develop pressure ulcers at lower pressures than those not exposed to friction [15]. Friction can occur from skin rubbing against rough surfaces, for instance, when being pulled up in bed, sliding across sheets or moving repetitively as may occur with spasticity. Shearing forces occur when the skin adheres to bed linens while the underlying tissues slide down, causing vessels vertical to the skin to torque or tear, resulting in deep tissue injury. Nutritional status is an intrinsic risk factor causing the skin and underlying tissue to be more or less vulnerable to the effects of pressure. One prospective study identified dietary intake of protein and calories to be more indicative of pressure ulcer development than serum albumin and other biochemical or anthropometric markers [16], and most studies identify one or more nutritional markers as being pivotal to pressure ulcer development.

Evidence-Based Care The United States Public Health Service, Agency for Health Care Policy and Research (AHCPR) mandated the development of clinical practice guidelines for selected areas of patient care during the early 1990s. Guidelines were developed in areas where the problem was frequently occurring

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or had a severe impact on patients or healthcare, where the cost of care was high and where there was a great deal of variability in practice. Multidisciplinary guideline development panels were convened to synthesize the scientific literature and make recommendations for practice based on the evidence. Two guidelines that emerged were: Pressure Ulcers in Adults: Prediction and Prevention [2] and Treating Pressure Ulcers [17]. The hallmark of these guidelines was a comprehensive review of the literature, creation of evidence tables, grading of evidence, and guideline recommendations based on evidence and clinical expertise. The guidelines had broad evaluation both in public forums and through clinical testing and organizational review prior to release. The AHCPR guidelines for pressure ulcers were developed a decade ago and there have been any number of attempts to re-evaluate or rewrite the guidelines or to make influential statements regarding patient care. Notably, the American Medical Directors Association, re-evaluated the guidelines and rewrote them with a greater focus on the nursing home population (1994), but did not conduct a substantial review of the literature. The National Pressure Ulcer Advisory Panel, in the United States, wrote influential statements on the assessment of pressure ulcers in dark-skinned individuals and wrote a position statement on staging healing ulcers that took a stance against reverse staging. One group, the Cochrane collaboration, developed a synthesis statement on support surfaces, reviewing only randomized controlled trials and ignoring other research methods. This review, likewise, did not consider covariates of outcome success. The European Pressure Ulcer Panel [18] and an Australian panel wrote more comprehensive guidelines grading evidence in a manner very similar to the US guidelines and concluding with nearly identical guideline recommendations. Small differences appear between the guidelines. The Australian guidelines were developed based on the principles of comprehensive review supported by the Joanna Briggs Institute for Evidence Based Practice. The guidelines, Pressure Ulcer Prevention and Treatment following Spinal Cord Injury, sponsored by the Paralyzed Veterans of America (2000) are the closest in methodology to the AHCPR guidelines. Interestingly, all of these efforts follow the same or a very similar template of recommendations and most support the same or similar recommendations as are summarized below. Additionally, a number of articles have also been written for the stated purpose of updating the guidelines [19, 20]. Yet, few substantive changes have been detected. An article in the Journal of the American Medical Association [21] recently stated that of all the guidelines developed in the early 1990s, the pressure ulcer guidelines remain most relevant. Sadly, there have not been major advances in the area of pressure ulcer prediction and prevention, but there have been some advances in treatment. Most of the new body of knowledge clusters around confirmation of risk factors, development and testing of dressings and support surfaces, and development and testing of vacuum-assisted therapy, electrical stimulation or topical substances. There have been few randomized controlled trials, even fewer studies that looked at the efficacy of preventive interventions or specific

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treatments and even fewer investigations of the effectiveness of guideline recommendations across settings. Several quality assurance-type studies demonstrated that guideline-based care reduced the incidence of pressure ulcers and saved money [22, 23], but more recent evidence shows that US hospitals, physicians and nurses have many opportunities to improve care related to pressure ulcer prediction and prevention [24]. The area of pressure ulcer prevention and treatment is in need of scientific advancement, as outlined in statements by Bergstrom and colleagues at the conclusion of the AHCPR guideline development process (1994) and more recently by the National Pressure Ulcer Advisory Panel [25].

Evidence-Based Care for Prevention Recommendations for the prediction and prevention of pressure ulcers that appear in most guidelines, representing the best evidence combined with the best clinical judgment of international experts, are detailed below. Figure 4.2 shows a visual display of the conceptual organization, procedural flow, decision points and preferred management as described in the AHCPR guideline [2].

Fig. 4.2. An algorithm presenting an overview of approaches for preventing pressure ulcers

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Risk Assessment Most guidelines recommend that bed- or chair-bound individuals should be assessed for risk of developing pressure ulcers on admission to a care setting and at periodic intervals that make sense based on the rapidity with which the patient's condition is expected to change within the setting. Most guidelines detail the list of risk factors associated with pressure ulcers. Mor demonstrated that as the number of risk factors increase, the incidence of ulcers increases [1]. In order to use a list of risk factors to guide assessments, a check list of risk factors should be generated and clinicians should denote the presence or absence of the risk factor, coupled with clinical intuition as to the point at which risk is present and must be treated. The list of risk factors does not offer guidance to the specific cut-off point for risk or to specific treatments that should be instituted, and while favoured by several of the guidelines over formal risk assessment, this method has never been tested for reliability, validity or clinical utility. Risk assessment tools based on conceptual risk factors that cut across many diagnoses, patient characteristics, physiological states and other risk factors are easier to use with consistency. One commonly used one-page risk predictor tool, the Braden Scale for Predicting Pressure Sore Risk (copyright Braden and Bergstrom, 1988) [26±28] assesses an individual for the presence and severity of risk factors and derives a score for overall risk. This total risk score identifies those requiring preventive interventions, but training and clinical judgment is pivotal to the successful use of this or any other clinical tool. The subscale scores direct attention to specific risk factors needing attention and the level of intervention needed. The Braden Scale has been tested more and with better results than the Norton, and Waterlow scales, the next most frequently used tools [29, 30]. The use of a formal risk assessment tool may level the playing field, providing experienced and less experienced clinicians with an opportunity to consider risk factors consistently. Regardless of the method used for risk assessment, clinical judgment is essential. Formal risk assessment tools are designed to detect those most commonly occurring risk factors, but specific patient-centred factors may increase or decrease that risk. The only purpose of risk assessment is to identify persons at risk and to facilitate the development of a plan of care. Bergstrom and colleagues [31] demonstrated that in the absence of formal, documented risk assessment, conscientious physicians and nurses were likely to underestimate who was at risk and were likely to under prescribe basic preventive strategies such as turning or the use of support surfaces. Bates-Jensen and colleagues [32] likewise demonstrated that subjects with an admission risk assessment were more likely to have documented preventive interventions (76%) than those without risk assessment (14%). It is critical that the plan of care be developed and instituted promptly based on patient risk factors. Gifford and colleagues demonstrated that earlier development of a plan of care resulted in fewer ulcers (unpublished data). Risk assessment helps to identify mobility and activity and sensory

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deficits which require attention to mechanical loading and support surfaces, as well as good skin care. Identification of excessive moisture or nutritional deficits focuses attention on preventing and managing these deficits and directs the caregiver to provide good skin care.

Skin Assessment Skin assessment should be done on admission and daily thereafter, with the results being documented. It is important, when assessing dark-skinned individuals, to employ careful visual inspection with good lighting and tactile inspection of vulnerable areas (AHCPR, 1992; http://www.npuap.org). Tactile inspection is done to detect changes in temperature, and to detect induration. While there are no published data to support the efficacy of this practice, early identification of abnormal findings provides an opportunity to redouble preventive efforts. Skin Care. It is important to maintain personal hygiene, keeping the skin clean and dry, minimizing factors that cause dryness, such as low ambient humidity, bath water that is too warm, harsh soaps and too frequent bathing. Moisturizing lotions should be used to prevent dryness and cracking of the skin. Preferences of the patient for frequency and method of bathing should be considered. Moisture. Minimize exposure of the skin to moisture from incontinence, perspiration or wound drainage. Assess and treat causes of urinary and faecal incontinence and provide opportunities for bowel and bladder training when appropriate. When exposure to moisture continues, use underpads or briefs that wick moisture away from the skin, or use moisture barriers to protect the skin. While there is evidence to show that the new disposable briefs do wick away moisture, clinical observation and judgment dictate that the skin be exposed to air at intervals to prevent the accumulation of moisture and heat.

Managing Pressure The goal of managing pressure is to reduce pressure and the length of time tissue over bony prominences is exposed to pressure with the potential for ischaemia or decreased blood flow. Exposure to the effects of pressure should be minimized through the use of appropriate support surfaces, frequent repositioning, the use of pillows and wedges and through avoiding lying directly on the trochanter and sitting with the head of the bed elevated for extended periods of time. While there are many studies in the literature that test support surfaces, studies comparing surfaces with like properties are rare. Studies have shown that high-density foam replacement

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mattresses tested against a variety of static surfaces such as overlays, in studies of variable rigor, demonstrate that the replacement mattresses are generally superior to standard, plastic-covered mattresses and standard foam or circulating air overlays [33]. The properties of the support surface, including life expectancy of the surface, pressure redistribution, effectiveness of skin moisture and temperature control, product service requirements, fail-safety, infection control, flammability, and contribution to friction, should be studied uniformly in tests of such surfaces [19]. An algorithm for clinical decision making that appeared in the AHCPR (1992) guideline is presented in Fig. 4.3. In addition to selecting the appropriate surface upon which to care for the patient, it is important to focus on other interventions, since pressure ulcers have been reported to develop even when the patient is cared for on a pressure reducing support surface. Patients should be turned at least every 2 h according to a written schedule according to the plan of care and goals for the patient even when a special mattress or bed is used. The every 2 h rule emerged from the work of Norton and associates [34] with elderly persons in the early 1960s. An observational study demonstrated that those who were turned every 2± 3 h developed fewer ulcers than those turned every 8 h or less often. The evidence supporting this guideline recommendation is weak, but it has become the standard of care world wide and should be continued until new evidence emerges that different intervals are appropriate. One study by Defloor [35] suggests that when foam replacement mattresses are used, turning every 3±4 h may be as effective as turning every 2 h on a standard hospital mattress. The study did not evaluate these findings in relation to level of patient risk. All at- risk patients were considered to be at high risk, and since the data have not been replicated, caution should be used when considering these data for practice implications. This is clearly an area requiring additional investigation. Pillows, wedges and other materials that aid in maintaining position and providing support should be used as needed. When the patient can be turned from side to side without lying on a pressure ulcer, static surfaces may be sufficient to prevent pressure ulcers. When the patient has multiple ulcers or when the patient cannot be turned due to physiological instability, a low-air-loss or air-fluidized bed should be considered. An algorithm to support decisions for support surface selection appears in Fig. 4.3. It should be noted that, pressure ulcers may develop when the patient is on an air-fluidized bed. Heels should be elevated on a pillow sufficient to raise the heels off the support surface, providing complete pressure relief [36]. Relief of heel pressure is important even on support surfaces purporting to reduce pressure. Abu-Own and colleagues [37] demonstrated that even on a low-air-loss surface, heel blood flow decreases in healthy subjects and patients when resting on the support surface. Furthermore, patients should be positioned according to the 308 rule to avoid lying directly on the trochanter. The head of the bed should not be elevated above 308 for longer than necessary since the trochanter and is-

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chial tuberosities place a great deal of pressure on the overlying tissues in these positions. Studies by Colin and associates [38, 39] confirm that pressure on the trochanter decreases tcPO2 and increases tcPCO2 to the underlying tissues, as does sitting with the head of the bed elevated.

Fig. 4.3. An algorithm to guide decision making regarding the selection of support surfaces [adapted from 51]

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Lifting devices that facilitate moving patients up in bed or turning them from side to side should be used to reduce exposure to friction and to prevent injury to carers. Donuts or rubber rings, because they create areas of reduced pressure, should not be used. Cushions that reduce pressure during seating and increase sitting stability should be used, but time in the sitting position should be minimized.

Nutrition for Prevention Maintaining and improving the nutritional status of patients is thought to increase the tissue tolerance for pressure by maintaining tissue integrity and providing substrates for repair of damaged tissues. Retrospective studies have demonstrated an association between low serum albumin and low haemoglobin, decreases in body weight over short periods of time, and very low or very high body mass index. One prospective study of dietary intake found that the current dietary intake of protein and calories was a more important predictor of pressure ulcer development than either serum albumin or anthropometric indices [16]. There are no studies reported in the literature that show that a specific level of nutritional support can prevent ulcers. Attempts to study the role of dietary intake in the prevention of pressure ulcers must be carried out in conjunction with other preventive measures though to appreciate changes in pressure ulcer development or healing. Until such studies are available, every effort should be made to assess dietary intake and nutritional requirements on admission and at intervals consistent with changes in patient condition, to provide adequate food to meet nutritional needs and to engage in creative approaches to stimulating dietary intake. When intake is inadequate, dietary supplementation should be considered to improve dietary intake, as long as this supplementation is not contraindicated by other care requirements or advanced directives that preclude the use of feeding tubes. Surprisingly, little research has been done to inform practice in the area of nutritional support related to pressure ulcers.

Evidence-Based Care for Managing Pressure Ulcers There are several components to the management of pressure ulcers included in most guidelines. These components include accurate and ongoing wound and patient assessment, wound care including cleansing, debridement, selection of dressings and adjuvant therapies. Pressure ulcers should be assessed on admission and at every dressing change, considering and documenting the dimensions (length, width, depth, shape), location, presence of eschar or necrotic tissue, amount and odour of exudates and presence or absence of granulation tissue. Pressure ulcers should be staged according to the recommendations of the National

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Pressure Ulcer Advisory Panel (http://www.npuap.org.) or a similar standard statement, and a formal documentation tool such as the Pressure Sore Status Tool (PSST) [40] or the Pressure Ulcer Scale for Healing (PUSH) [41] should be used to ensure consistency in documentation. Once the wound is assessed, a plan of care should be devised and written. Ongoing assessment, at every dressing change or once a week, whichever is the shorter interval, should guide the clinician's decisions to continue or change the plan of care. Continuity of care is important, but assessment of progress determines when to continue or when to alter the plan of care. Cleansing. The wound should be cleansed initially and at every dressing change to reduce bacterial burden and to remove devitalized tissue and other wound exudates. Normal saline without a preservative should be used to irrigate wounds since it is reported to be non-cytotoxic. Cleansing agents with preservatives or inert carriers may be cytotoxic, and should be avoided, along with, antiseptics (e.g. Betadine) that may be toxic to regenerating cells. Hellewell and colleagues [42] reported the toxicity of several wound cleansers, finding that antiseptics were the most cytotoxic. Irrigation of the wound with the cleansing agent may be achieved with squeeze bottles, syringes, battery-powered devices or the like. Since the goal of cleansing is to remove exudate and sloughing tissue from the wound, it is recommended that some gentle mechanical force or pressure be used to cleanse the wound, rather than simply spraying the wound and patting it dry. Rodeheaver [20] recommended pulsatile lavage to loosen wound debris combined with gentle suction to remove cleansing agents and debris. When wounds are populated with significant eschar, whirlpool therapy can be considered for cleansing. One small study of 23 patients by Burke and colleagues [43] demonstrated improved wound healing of stage 3 and 4 ulcers with daily whirlpool treatments. It is important that appropriate infection control protocols are in place to maintain the cleanliness of whirlpools. Throughout the wound cleansing and dressing stages, strict attention must be paid to implementing precautions to protect against blood-borne pathogens. Debridement. Debridement, or the removal of necrotic tissue and wound debris, should be done when cleansing alone is not sufficient to remove devitalized tissue from the wound bed. Debridement is appropriate when wound cleansing is inadequate to remove sloughing and devitalized tissue from the ulcer and should be carried out with consideration of the status of the ulcer and the condition of the patient. An exception to the debridement recommendation is when large heel ulcers covered by eschar present without erythema of surrounding tissues, fluctuance or drainage. These heel ulcers should not be debrided, but rather be evaluated frequently. When debridement is necessary, the method most appropriate for the given patient's condition should be selected. Autolytic, mechanical, chemical or sharp debridement may all be appropriate. Autolytic debridement is achieved using an occlusive or semi-occlusive dressing that retains mois-

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ture and liquefies necrotic tissue by phagocytosis, and tissue enzymes. Mechanical debridement is achieved non-selectively using physical force such as wet-to-dry dressings, lavage, whirlpool and other methods to loosen foreign materials and contaminated tissues and healthy tissue as well. Chemical debridement employs topical proteolytic or collagenolytic enzymes to loosen and liquefy eschar, slough and wound debris. It is important that clinicians reassess the wound periodically to determine when debridement is complete and to discontinue treatments that may destroy granulating tissue. Sharp debridement selectively removes necrotic tissue, using sterile instruments, but without anaesthesia and with little or no bleeding. This is closely related to surgical debridement, in which much more aggressive excision may be done. Sharp and surgical debridement are the most appropriate when the bacterial load of the wound may evolve into spreading cellulites and sepsis. In all cases, it is important to consider the pain and discomfort to which the patient is exposed and to manage the pain effectively. Dressings. The basic principle in the selection of a dressing is to remember that wounds heal better in a moist environment. The goal of care is to select a dressing that keeps the wound bed moist, the surrounding tissue dry and controls exudate without desiccating the ulcer bed. Deep wounds and wounds with sinus tracts and undermining should be packed loosely to eliminate dead space. There is no research supporting the use of one specific brand of dressing over another, despite the number of new dressings brought to the marketplace. It has, however, been demonstrated that dressings maintaining a moist wound environment are associated with better healing than dry dressings [44, 45]. Moisture-retaining dressings have been associated with a reduction in needed caregiver time and overall cost effectiveness [46]. It is important to remember that wet-to-dry dressings are not a variant of a moist wound environment; as the dressings dry, they provide indiscriminate mechanical debridement. In the future, smart dressings that notify of prolonged exposure to pressure, exposure to moisture, or specific substrates or bacteria in the wound may emerge; if so, they will be a welcome addition to care. Adjuvant Therapies. A number of adjuvant therapies to promote wound healing have good evidence to support clinical implementation, and others are currently emerging. Electrical stimulation has demonstrated efficacy for promoting closure of stage III and IV ulcers when combined with other care [48±50]. Vacuum-assisted therapy is showing promise for promoting healing of stage III and IV ulcers, but no data have emerged to clearly demonstrate the efficacy and to direct clinicians regarding the end point of therapy. The lack of controlled studies prevents the recommendation of most adjuvant therapies. Manufactures and clinicians can contribute to pressure ulcer care by focusing on controlled studies.

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Future Research It is clear from the recommendations of guideline panels and most authors writing about pressure ulcers that there is a need for multi-site efficacy studies of specific products and treatment modalities. These studies must have adequate statistical power to draw conclusions and make recommendations for practice. Studies testing the efficacy of like products (similar mattresses, dressings, adjuvant therapies) from different manufacturers would be particularly helpful in clinical selection of the best, most cost-effective products. Standard care plans should be developed based upon specific risk factors. These care plans should be tested for efficacy and to characterize the patient's response to the care plan. Characterization would provide additional information about circumstances for using the plan of care, the efficacy for specific individual characteristics and the time to healing. Testing a protocol or a comprehensive care plan would provide data that would permit conclusions about the effectiveness of the treatments, the degree of compliance with recommendations, and outcomes of clinicians. Most efficacy data only support the selection of one product over another, but effectiveness research also needs to evaluate a composite of treatments performed for prevention or treatment to permit evaluation of outcomes when protocols are used. Recent data suggest that increased time for nurses to provide care results in improved patient outcomes. This relationship between staffing and patient outcomes needs to be tested in prospective studies where interventions can be documented. It is important to evaluate the role of other therapists and providers as well, in order to determine judicious use of consultants and consultant recommendations. A long list of important studies that would contribute to knowledge development and clinical practice in the area of pressure ulcers could be generated. This is a fruitful area for new and seasoned investigators alike. The challenge is in identifying those studies that will most rapidly advance the science and provide an opportunity for more enlightened practice. Guideline summaries that synthesize the literature to date and point to gaps in the current knowledge base would provide an excellent starting point.

References 1. Mor V et al. (1998) Benchmarking quality in nursing homes: the Q-Metrics system. Can J Qual Health Care 14:12±17 2. Bergstrom N, Allman RM, Carlson CE, et al. (1992) Pressure ulcers in adults: predication and prevention. Clinical practice guideline, Number 3. AHCPR Publication No. 92-0047. Agency for Health Care Polich and Research, Public Health Service, U.S. Department of Health and Human Services, Rockville, MD 3. Cuddigan J, Ayello EA, Sussman C, Baranoski S (eds) (2001) Pressure ulcers in America: prevalence, incidence, and implications for the future. National Pressure Ulcer Advisory Panel, Reston, VA

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4. Brooks EL, Duncan GW (1940) Effects of pressure on tissues. Arch Surg 40:696±709 5. Husain T (1953) An experimental study of some pressure effects on tissues with reference to the bed-sore problem. J Pathol Bacteriol 66:347±358 6. Kosiak M (1959) Etiology and pathology of ischemic ulcers. Arch Phys Med Rehab 40:62±68 7. Daniel RK, Priest DL, Wheatley DC (1981) Etiologic factors in pressure sores: an experimental model. Arch Phys Med Rehab 62:492±498 8. Allman RM, Goode PS, Patrick MM, Burst N, Bartolucci AA (1995) Pressure ulcer risk factors among hospitalized patients with activity limitation. JAMA, 273 (11), 865±870 9. Bader DL, White SH (1998) The viability of soft tissues in elderly subjects undergoing hip surgery. Age Ageing, 27:217±222 10. Nicholson PW, Leeman AL, O'Neill CJA, Dobbs SM, Deshmukh AA, Denham MJ (1988) Pressure sores: Effect of Parkinson's disease and cognitive function on spontaneous movement in bed. Age and Ageing 17:111±115 11. Schnelle JF, Adamson GM, Cruise PA, Al-Samarrai N, Sarbaugh FC, Uman G, Ouslander JG (1997) Skin disorders and moisture in incontinent nursing home residents: Intervention implications. J Am Geriatr Soc 45:1182±1188 12. Horn SD, Bender SA, Bergstrom N, Cook AS, Ferguson ML, Rimmasch HL, Sharkey SS, Smout RJ, Taler GA, Voss AC (2002) Description of the National Pressure Ulcer Long-Term Care Study. J Am Geriatr Soc 50:1816±1825 13. Needleman J, Buerhaus P, Mattke S, Stewart M, Zelevinsky K (2002) Nurse staffing and quality of care in hospitals in the United States. N Engl J Med 346:171±175 14. Braden BJ, Bergstrom N (2000) A conceptual schema for the study of the etiology of pressure sores. Rehab Nurs 25:105±110 15. Dinsdale SM (1974) Decubitus ulcers: role of pressure and friction in causation. Arch Phys Med Rehab 55:147±152 16. Bergstrom N, Braden B (1992) A prospective study of pressure sore risk among institutionalized elderly. J Am Geriatr Soc 40:747±758 17. Bergstrom N, Bennett MA, Carlson CE, et al. (1994) Treatment of pressure ulcers. Clinical practice guideline, number 15. U.S. Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research, Rockville, MD. AHCPR Publication No. 95-0652 18. European Pressure Ulcer Advisory Panel (EPUAP) (1999) Guideline on treatment of pressure ulcers EPUAP, Oxford (available from: http://www.epuap.org, accessibility verified on 27 February 2003) 19. Maklebust J (1999) An update on horizontal patient support surfaces. Ostomy/Wound Management 45[Suppl 1A]:70S±77S 20. Rodeheaver GT (1999) Pressure ulcer debridement and cleansing: a review of current literature. Ostomy/Wound Management 45[Suppl 1A]:80S±85S 21. Shekelle PG, Ortiz E, Rhodes S, Morton SC, Eccles MP, Frimshaw JM, Woolf SH (2001) Validity of the Agency for Healthcare Research and Quality Clinical Practice Guidelines: How quickly do guidelines become outdated? JAMA 286:1461±1467 22. Horn S, Ashton C, Tracy D (1994) Prevention and treatment of pressure ulcers by protocol. In Horn S, Hopkins D (eds) Clinical practice improvement: a new technology for developing cost-effective quality health care. Faulkner & Gray, New York

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23. Bergstrom N, Braden B, Boynton P, Bruch S (1995) Using a research-based assessment scale in clinical practice. Nurs Clin North Am 30:539±551 24. Lyder CH, Preston J, Grady JN, Scinto J, Allman R, Bergstrom N, Rodeheaver G (2001) Quality of care for hospitalized medicare patients at risk for pressure ulcers. Arch Intern Med 161:1549±1554 25. Cuddigan J, Frantz RA (1998) Pressure ulcer research: pressure ulcer treatment: a monograph. National Pressure Ulcer Advisory Panel. Adv Wound Care 8:46±48 26. Bergstrom N, Braden B, Kemp M, Champagne M, Ruby E (1998) Predicting pressure ulcer risk: a multi-site study of the predictive validity of the Braden Scale. Nurs Res 47:261±269 27. Bergstrom N, Braden B, Laguzza A, Holman V (1987) The Braden Scale for predicting pressure sore risk. Nurs Res 36:205±210 28. Braden BJ, Bergstrom N (1994) Predictive validity of the Braden Scale for pressure sore risk in a nursing home population. Res Nurs Health 17:459±470 29. Pang SM, Wong TK (1998) Predicting pressure sore risk with the Norton, Braden and Waterlow scales in a Hong Kong rehabilitation hospital. Nurs Res 47:147±153 30. Van Marum RJ, Ooms ME, Ribbe MW, Van Eijk J (2000) The Dutch pressure sore assessment score or the Norton scale for identifying at-risk nursing home patients? Age Ageing 29:63±68 31. Bergstrom N, Braden B, Kemp M, Ruby E (1996) Multi-site study of incidence of pressure ulcers and the relationship between risk level, demographic characteristics, diagnoses, and prescription of preventive interventions. J Am Geriatr Soc 44:22±30 32. Bates-Jensen BM, Cadogan M, Jorge J, Schnelle JF (2003) Standardized quality assessment system to evaluate pressure ulcer care in nursing homes. J Am Geriatr Soc 51:1194±1202 33. Whittemore R (1998) Pressure reduction support surfaces: a review of the literature. J Wound Ostomy Continence Nurs 25:6±25 34. Norton D, McLaren R, Exton-Smith AN (1962) An investigation of geriatric nursing problems in hospital. Churchill Livingstone, New York 35. Defloor T (2001) Wisselhouding, minder frequent en toch minder decubitus. Tijdschr Gerontol Geriatr 31:174±177 36. Sideranko S, Quinn A, Burns K, Froman RD (1992) Effects of position and mattress overlay on sacral and heel pressures in a clinical population. Res Nurs Health 15:245±251 37. Abu-Own A, Sommerville K, Schurr JH (1995) Effects of compression and type of bed surface on the microcirculation of the heel. Eur J Vasc Endovasc Surgy 9:1995 38. Colin D, Abraham P, Preault L (1996) Comparison of 90o and 30o laterally inclined positions in the prevention of pressure ulcers using transcutaneous oxygen and carbon dioxide pressures. Adv Wound Care 9:35±38 39. Colin D, Loyant R, Abraham P (1996) Changes in sacral transcutaneous oxygen tension in the evaluation of different mattresses in the prevention of pressure ulcers. Adv Wound Care 9:25±28 40. Bates-Jensen BM, Cadogan M, Osterweil D, Levy-Storms L, Jorge J, A-Samarrai N, Grbic V, Schnelle JF (2003) The minimum data set pressure ulcer indicator: does it reflect differences in care processes related to pressure ulcer prevention and treatment in nursing homes. J Am Geriatr Soc 51:1203±1212

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41. Stotts NA, Rodeheaver GT, Thomas DR et al. (2001) An instrument to measure healing in pressure ulcers: development and validation of the Pressure Ulcer Scale for Healing (PUSH). J Gerontol 56:M795±799 42. Hellewell TB, Major PA, Foresman PA (1997) A cytotoxicity evaluation of antimicrobial and nonantimicrobial wound cleansers. Wounds 9:15±20 43. Burke DT, Ho CH, Saucier MA (1998) Effects of hydrotherapy on pressure ulcer healing. Arch Phys Med Rehab 77:394±398 44. Xakellis GC, Chriscilles EA (1992) Hydrocolloids versus saline gauze dressings in treating pressure ulcers: a cost effective analysis. Arch Phys Med Rehab. 73:463±469 45. Colwell JC, Foreman MD, Trotter JP (1993) A comparison of the efficacy and cost effectiveness of two methods of managing pressure ulcers. Decubitus 6:28±36 46. Bolton LL, van Rijswijk L, Shaffer FA (1997) Quality wound care equals costeffective wound care: A clinical model. Adv Wound Care 10:33±38 47. Baker LR, Chambers R, DeMuth S (1997) Effects of electrical stimulation on wound healing in patients with diabetic ulcers. Diabetes Care 20:405±412 48. Wood J, Evans P, Schallreuter K (1993) A multicenter study on the use of pulsed low-intensity direct current for healing chronic state II and III decubitus ulcers. Arch Dermatol 129:999±1009 49. Stefanovska A, Vodovnik L, Benko H (1993) Treatment of chronic wounds by means of electric and electromagnetic fields. 2. Value of FES parameters for pressure sore treatment. Med Biol Eng Comput 31:213±220 50. Griffin J, Tooms R, Mendius R (1991) Efficacy of high-voltage pulsed current for healing of pressure ulcers in patients with spinal cord injury. Phys Ther 71:433±442 51. Kemp MG, Krouskop TA, Garber BS, Carlson CE (1992) Guideline: mechanical loading and support surfaces. Agency for Health Care Policy and Research, pp 137±148

The Measurement of Interface Pressure Ian Swain

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Introduction There are a number of factors that can predispose an individual to a high risk of developing pressure ulcers. These can be divided into external factors, including pressure, shear, time, temperature, humidity and their interactions, and internal factors, which determine the level of loading tolerated by tissues before damage occurs [1]. The internal factors can be affected by the underlying disease such as diabetes or certain neurological conditions in which the tissues are more liable to be damaged by a given level of pressure and are dealt with elsewhere in this book. This chapter is primarily concerned with the external factors, in particular pressure, which can be affected by a loss of muscle bulk and tone as in flaccid paraplegia, or by the weight loss associated with the latter stages of cancer. Although the majority of this chapter will deal with the interface pressures measured on mattresses and cushions it should be remembered that pressure ulcers can occur in other situations. They may be found on the feet due to poorly fitting footwear, especially if the patient is diabetic, on limb stumps due to prostheses, or under orthoses, especially if the orthosis is exerting significant force to try to prevent spinal or bony deformity. There are, basically, only two ways associated with pressure in which a support surface can operate in order to reduce the probability of a pressure ulcer developing. Firstly, there are static systems which seek to minimise the interface pressure by increasing the contact area, and secondly dynamic systems which produce an alternating action that subjects the tissues to periods of high pressure followed by periods of low pressure during which it is anticipated that the pressure is sufficiently low to enable blood flow to return. The development of accurate pressure-measuring systems is important in assessing such support systems. However their exclusive use in determining risk of breakdown is critically dependent on a reliable indicator of safe pressure, or band of pressures, in association with time [2], that would be appropriate for all patients at risk. This remains a ªholy grailº for medical engineers involved in the prevention of pressure ulcers. Many attempts have been made to determine the minimal degree and duration of compression that will consistently produce tissue damage [3±5]. Often quoted as a cut-off figure is 32 mmHg, which is the capillary pressure as measured by Landis [6]. However, this value, measured in 1930, was determined in a nail fold capillary at

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heart level and it is therefore difficult to see how this relates to the external pressure needed to stop blood flow in capillaries when a person is sitting on a cushion or lying on a mattress. In such cases the picture is much more complicated, as there are supporting structures such as collagen and muscle fibres around the capillaries which will serve to distribute the applied load. In addition, the blood pressure in the capillary will vary due to both systemic blood pressure and the hydrostatic head of blood, which will depend upon the person's posture. What is undeniable, however, is that high pressures are sustainable for short times only and, if maintained, will lead to tissue breakdown.

Interface Pressure Measurement History Despite the fact that a `safe' interface pressure cannot be easily determined, the vast majority of researchers accept that high interface pressures are a major contributory factor in the development of pressure ulcers. One of the first to do so, in 1961, was Kosiak [7], who subjected rats to a variety of different pressure/time loading regimes and looked at the rate of pressure ulcer formation. His earlier work had shown that pressure measured under the ischia on a foam cushion was of the order of 150 mmHg [8] and therefore he concluded that complete ischaemia of tissues over the bone was only a matter of time, with an unrelieved pressure of only 40 mmHg being sufficient to cause ischaemia [7]. The importance of the pressure/ time relationship was further explored by Reswick and Rogers [2], who produced the famous graph shown in Fig. 5.1, which was based on 980 observations. They strongly stated, however, that this curve is a guideline, based on much experience but relatively few controlled measurements. An early review of methods of measuring interface pressure was undertaken by Ferguson-Pell et al. in 1976 [9]. At that time pressure-measuring devices fell into three broad categories. Firstly, some devices consisted of thin sheets of various materials treated with inks or chemicals. These have the advantage of giving a map of the pressure distribution but are difficult to quantify, subject to in-plane forces and also sensitive to rate of loading and temperature. Secondly there are devices that consist of air cells which have electrical contacts on the inside. Inflation pressure is measured and increased until the surfaces of the cell part, which can be demonstrated by an indicator bulb. The inflation pressure in the cell at this point is taken to be equal to the interface pressure. The final type in use at that time were strain-gauge diaphragm transducers, some of which were commercially available for fluid measurements. In addition, research was being undertaken in a number of centres to develop thin capacitive, resistive or inductive sensors. The conclusions from this review almost 30 years ago are still true today, namely that the sensor must give a useful output over the range 10±

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Fig. 5.1. Allowable pressures vs time of application for tissues under bony prominences. Curve gives general guidelines and should not be taken as absolute. Adapted from [2]

250 mmHg. Time dependence must be minimal or at least well defined and repeatable, and the sensor must be smaller than the radius of curvature of the body area under investigation. Finally, calibration is problematic and consideration must be given to the thickness and flexibility of the transducer, compliance of the loading interfaces and the possibility of the sensitivity of the transducer to forces other than those in the normal direction. Any system designed to measure interface pressure will inherently have an effect on the very parameter that it is attempting to measure. There are a number of different systems that have been developed over the years ranging from single sensors, such as the original 28-mm Scimedics system (Talley Medical, Romsey, Hants, UK) which needed to be manually inflated to record pressures, to a number of systems with multi-element arrays which are capable of capturing data in real time and producing an image on a computer screen. Various researchers have advocated different systems, although to date there is no `gold standard'.

Practical Considerations Two main factors must be considered when measuring interface pressure. In particular the sensor must be correctly located under the relevant bony prominence, and also its presence must not introduce errors which would mask any difference between the support systems being evaluated. As will be described, interface pressure has been shown to be significantly affected both by the positioning of the subject and by any object between the subject's skin and the support surface, particularly if that object is inflexible

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and cannot adapt to the shape of the patient/surface interface. In practice these two factors are largely mutually exclusive, as the large-array systems have the advantage of many sensors, so that the point of maximum pressure can be determined easily, but have the disadvantage that if they are inflexible they will affect the surface, especially if the surface deforms in more than one dimension, as in the case of a low-air-loss or fluidised-bead bed. If individual sensors are used then errors will be reduced if they are smaller than the area of interest; however, they will need to be accurately positioned to record the pressure exerted on the area of interest. If the sensor is larger than the area of interest it will act as an additional support, particularly if the sensor is inflated, and will therefore significantly change the patient/surface interface. Even if the sensor is of the correct size and type and is accurately placed, it should be realised that any readings taken are only a `snapshot' of that particular situation and will vary with time and with any change in posture of the patient.

Comparison and Analysis of Different Systems There have been few reported comparisons of different pressure measuring systems. Allen et al. [10, 11] looked at the repeatability and accuracy of the Talley SA500 Pressure Evaluator with both the 28-mm and 100-mm sensor pads (Talley Medical, Romsey, Hants, UK). This is an electropneumatic device in which the pressure needed to inflate an air sac is increased until two contacts on the internal faces of the air sac are broken. This pressure is then recorded as the interface pressure. They also evaluated the DIPE (Next Generation, CA, USA) and found the Talley 28-mm sensor was the most accurate. Ferguson-Pell and Cardi [12] compared two arrays, the Force Sensing Array (FSA), with 225 sensors (Vista Medical, Winnipeg, Canada) and the Tekscan, with 2064 sensors, and the Talley Pressure Monitor (TPM), with 96 sensors (Talley Medical). The TPM differs from the other two, consisting of small arrays of sensors as well as individual sensors which can be directly located on the skin surface. By contrast the FSA and Tekscan are large arrays, typically 500 mm ´ 500 mm, which cover the whole area of interest. The authors found that the TPM was the most accurate, stable and reproducible of the systems tested but was limited in its ease of use, speed and data presentation [12]. The FSA was well rated in clinical applications but demonstrated pronounced hysteresis (+19%) and creep (4%). The Tekscan system also showed substantial hysteresis (+20%) and creep (19%) but was preferred by clinicians for its real-time display capabilities, resolution and display options. Gyi et al. [13] undertook a detailed critique of the TPM, a more recent derivative of the Oxford Pressure Monitor [14] which examines the pressure/flow characteristics of the air needed to inflate a small air sac. This has been shown to give good correlation with the Talley SA 500 [15]. These authors identified a major disadvantage of this system in that it did not give readings in real time as it samples one sensor element approximately

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every second and therefore each sensor is sampled only every 90 s if all 96 sensors are connected. Other findings were that the system was improved if the sensor elements were more tightly packed and that errors could occur if the sensors were placed on a curved surface, although the errors were small if the radius of curvature was less than 20 mm. In addition, if only 75% of the sensor face was covered then the reading obtained was 82% of the correct value. The authors are unaware of any other evaluations of this type and it is clear that similar studies are required to quantify errors associated with the measurement of interface pressure. Since the studies quoted above there has been little work on the comparison of different pressure measuring systems despite the fact that a number of new systems have appeared on the market. In addition, at the time of writing this chapter, the TPM is no longer available for purchase but is still available for hire, directly from Talley. Table 5.1 shows the range of pressure-measuring equipment currently available in the UK. More information can be obtained from any of the companies' websites. The only recent evaluation of pressure-measuring systems was by Diesing et al. [16], who compared the FSA, Novel and X sensor. Their conclusions were that all systems underestimated the force applied on a small contact area. The minimum contact area for an accurate reading was in the range between 4.5 cm2 and 19.6 cm2, depending upon the system. However all showed good linearity and the authors felt that all were excellent tools for clinical use but all were inclined to underestimate the pressure under small bony prominences. They also felt that it was not possible to compare pressures taken on two different systems.

Factors to Consider When Measuring Interface Pressure As well as the inherent sources of error present in any specific measurement system, measurement of interface pressure is made more difficult by the variability that is introduced by the experimental procedures adopted. This variability is due to subject positioning, the choice of measuring system used, curvature and compliance of the subject/support surface interface, clothing etc. and is considerably greater than any inaccuracy in the measuring device itself, which is normally quoted to be of the order of 10% or 10 mmHg. Each of these will now be considered, although a more detailed account of these potential problems can be found in a recent paper by Swain and Bader [17].

Intersubject Variability As pressure is force per unit area it is obvious that the shape of a subject will have an effect on the interface pressure. The shape of the subject will depend on the skeleton, the quantity, tone and shape of the musculature

Capacitive

Seat Mattress

Seat 12.5´12.5 Hi-res 2.7´2.7

Up to 70,000 sensors s±1

0±220

Seat 2304 Bed 10,240 Hi-res 65k

10% or 10 mmHg

Computer

www.xsensor. com

Principle of operation

System

Sensor size (mm)

Sample rate

Range (mmHg)

No. of sensors

Quoted accuracy

Output device

Web address

www.vistamedical.nl

Computer

www.tekscan.com

Computer

Clinically Ô 3% Laboratory Ô 1%

over 2,000

up to 32´32

10%

Seat 0-200/1,000 Foot 0-7500

316,800 sensors s±1

3,072 sensors s±1

Bed 0±200 Foot 0±1500

Foot 5´5

Seat In shoe Dental

Resistive

Tekscan

Bed 19´50 Foot 9´16

Seat Back Bed In shoe Orthotist

Piezo-resistive

FSA

www.talleymedical.co.uk

Handheld digital gauge

Ô 2%

1

20-300

N/A

100 mm round 28 mm round

Individual sensor

Electro-pneumatic

Talley

www.clevemed. com

Handheld digital gauge

Ô 3 mmHg

1

0-125

N/A

25 or 62.5

Individual sensor

Pneumatic

Pressure

www.novel.de

Computer

Typically Ô 5%

Up to 2,304

Bed 0-200 Foot 0-1,800

Up to 20,000 sensors s±1

2.7´2.7 min 31´47 max

Seat Foot Specialist e.g. bike seat hand

Capacitive

Novel

z

X Sensor

Table 5.1. Comparison of commercially available interface pressure measuring systems

56 The Measurement of Interface Pressure

a

Variability Due to Anatomical Location and Patient Position

z

57

and the amount of subcutaneous fat. There have not been many studies to compare different groups although in general people with a low body mass index (BMI) are inclined to have higher interface pressures [18]. However, the effect that an individual's anatomy has on interface pressure is much more subtle, and even individuals with very similar body types can exhibit quite different interface pressures [17]. This can be demonstrated well from the baseline data on the standard King's Fund mattress obtained by the author in both Department of Health-funded and commercial trials [15, 19±22]. Therefore the range of interface pressures on various anatomical sites vary widely with the subjects' underlying anatomy, and, in my experience, it is not possible to predict the interface pressures from the person's body type. Interface pressures were measured on the King's Fund mattress at the most common locations for pressure ulcers by the author. These readings were made using elderly ambulant volunteers and were obtained from readings made during the production of the Department of Health Evaluation Reports PS1, PS2, PS3, PS4 and PS5 [19±24] and from 20 years' consultancy work for a great number of companies. Sacrum when semi-recumbent, backrest at 458 Trochanter, side lying, hips and knees at 608 Heels Ischial tuberosities when sitting on 3-in. standard cushion

62±107 mmHg (8.3±14.3 kPa) 6±156 mmHg (8.1±20.8 kPa) 107±213 mmHg (14.3±28.4 kPa) 60±146 mmHg (8±19.5 kPa)

Variability Due to Anatomical Location and Patient Position The human body is not a homogeneous structure and therefore the interface pressure will vary depending on the shape of the underlying bony structure at the point of interest, the amount of subcutaneous tissue covering that bone and the weight being supported. High-pressure points will therefore either be areas such as the heels when lying supine, where there is a small contact area, or the buttocks when sitting, where there is a large load combined with underlying bony prominences, the ischial tuberosities. If this contact area is further reduced by extensive loss of subcutaneous tissue, then the pressures will increase. However, when lying supine a person with normal pathology will have much lower interface pressures under the buttocks since the load is distributed over a larger area, and as the pelvis is rotated, compared to sitting, there are no obvious bony prominences in contact with the support surface. In this position more pressure will be ex-

58

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The Measurement of Interface Pressure

Fig. 5.2. The effect of footrest height on interface pressure

erted on the sacrum, particularly if the person is semi-recumbent. Therefore the person's posture will have a marked effect on the areas subjected to the highest pressures. For example a person sitting in a slumped position in a chair will often have the highest pressures recorded under the sacrum rather than under the ischial tuberosities. When comparing different products, it is essential to ensure repeatable positioning of the subjects, as failure to do so can lead to errors that are greater than the underlying differences between the products. This is best demonstrated by the results obtained during the Department of Health trial on wheelchair cushions [22, 23] (Fig. 5.2). This variability is also reported by other researchers. Koo et al. [25] found that in seated patients, interface pressure could increase from 88 to 146 mmHg ( from 11.7 to 19.5 kPa) on a Roho cushion and from 106 to 221 mmHg (from 14.1 to 29.5 kPa) on a PU foam cushion as the patient varied their position in the chair from leaning forward to leaning to the right. This indicates that the more conforming the cushion, the less effect posture has on interface pressure. Hobson [26] also found that posture and body orientation had a profound effect on body-seat interface variables and that posture is a factor that deserves increased research and clinical attention.

Variability Due to Underlying Pathology Expediency often requires that interface pressure readings are undertaken on healthy, young adult volunteers, often students, despite the fact that the vast majority of people at risk of pressure ulcers are elderly or those with chronic diseases, illness or disabilities. In those at risk there will not only be a change in shape at the patient-support interface due to loss in muscle tone, but the

a

Correlation Between Interface and Interstitial Pressures

z

59

skin will often have inferior mechanical properties and the body will be less able to adapt to the effects of pressure due to the underlying pathology. This is particularly the case if the underlying disease affects the normal circulatory control system, such as in multiple sclerosis and spina bifida. Of the few studies to compare the interface pressure of different groups, Brienza and Karg [27] showed that the type of cushion had a greater effect on subjects with SCI than it did with the elderly, but suggested that more research was still needed. Hobson [26] also noted that people with spinal cord injuries exhibited interface pressures between 6 and 46% higher than a control group of normal subjects. The Department of Health Evaluation Report, PS4 also measured interface pressure on a variety of users, including flaccid and spastic paraplegics, people following a cerebrovascular accident (CVA) and elderly ambulant volunteers, and showed that the ranking of products was significantly different for each of the groups. This will be considered in more detail in the section on mannequins versus normal volunteers.

Variability Due to Other Factors A static support surface is required to conform to the shape of the body so that the load can be distributed over a larger area, hence reducing the interface pressure. In a dynamic support surface, such as an alternating pressure mattress, it is essential that nothing affects the alternating action, so that when a given cell is deflated, the interface pressure is sufficiently low to enable blood flow to return to normal levels before the next period of high pressure when the cell is reinflated. In both types of systems the properties of any covering materials between the foam, air or gel of the cushion and the subject's skin will affect the interface pressure. If the covering material is too tight and inflexible then it will be inclined to hammock across the support surface, preventing deformation of the underlying core in static systems [19] and negating the alternating action in dynamic systems. The effect of the covering material is also of importance when advising the wheelchair- or chair-bound patient on the choice of clothing. Thus stretchy sports clothing will be far better for the patient than heavy materials like denim, which are non conforming and usually have thick seams and rivets in support areas. It is therefore essential that, as clothing will make a difference to the interface pressure, it is kept to a minimum and standardised in any product evaluations.

Correlation Between Interface and Interstitial Pressures As briefly discussed in the Introduction, the important parameter is not actually the interface pressure but the resultant pressure that is transmitted to the tissue. If this pressure is of sufficient magnitude, it can stop blood flow and lead to tissue necrosis. It is the fact that measurement of the in-

60

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The Measurement of Interface Pressure

ternal or interstitial pressure is difficult and inherently invasive that has lead to the widespread use of interface pressure as a parameter that can easily be measured in the clinical environment. Added to the difficulty in measuring interstitial pressure per se is the inherent complication that introducing a measuring device into the tissue is bound to have an effect. The exact position of the probe is critical and any location, whether just below the skin, adjacent to a bony prominence or in the middle of a muscle, will affect the results obtained. Few studies have attempted to compare interface and interstitial pressure, and it is difficult to compare the results that different groups have obtained. In 1984 Le et al. [28], using silicon pressure transducers in pigs, stated that they measured pressures that were between three to five times greater next to the bone than the applied interface pressure on the surface of the skin. Reddy [29], however, applying pressure with a cuff in a pig model and measuring interstitial pressure with a wick catheter 2±5 mm below the skin, showed that the interstitial pressure was only 65±75% of the applied pressure but increased to 100% when the tissue was oedematous. Dodd [30] also used a pig model and showed that 28±43% of pressure was transferred to the interstitium depending upon anatomical location, with the highest readings being over the sacrum. One of the few studies to undertake measurements on people was that by Sangeorzan et al. [31], who found that the displacement necessary to reduce TcPO2 to zero was significantly less over bone than it was over muscle. Their explanation was that skin over muscle tolerates greater locally applied loads and deformations because the pressure is lower within the tissue than when similar loads and deformations are applied to skin over bone.

Uses of Interface Pressure Measurement Pressure measurement systems can be used in two separate environments. Firstly in a clinical setting, typically associated with a seating clinic, in which interface pressure is used as an adjunct to risk assessment as well as providing an aid to clinical prescription. In this setting it can also be used to give biofeedback to the patient, providing evidence of postural factors associated with pelvic obliquity, tilt and rotation and the efficacy of pressure-relief regimens. Alternatively, it can be used in the laboratory to evaluate the relative performance of different pressure-reduction systems under controlled conditions.

Clinical There are two roles that interface pressure measurement has in the clinical environment: firstly in patient education, and secondly to determine that a cushion is suitable for a given individual. Patient education is of vital im-

a

Clinical

z

61

portance when dealing with groups of people at high risk, as unless the person is themself aware of the possible consequences of poor seating, poor posture and lack of attention to skin care, they stand a greater chance of developing pressure ulcers. It is perhaps interesting to draw an analogy with patients with hypertension who regularly visit their GP and hospital clinics to have their blood pressure measured, where the information obtained is used for clinical audit and to determine the effect of any change in medication. The very act of measuring blood pressure indicates to the patient that the professionals involved are concerned and are addressing the situation. Imagine the patients' concern if their blood pressure was never measured but their medication was still changed. It is all a question of relative risk, as although it is not known that a person with a given level of hypertension will have a myocardial infarction or a CVA within a given period of time, it is known that the probability of such an event is greater. It is the same with a person who is wheelchair dependent. We do not know that a given level of interface pressure will lead to skin breakdown in a given period of time. However, we do know that the greater the period of unrelieved pressure [2, 32], the greater the risk of developing pressure ulcers. In addition, with the increase in litigation and the implementation of clinical governance in the UK, measurement and recording of interface pressure could be regarded as being as essential activity for anyone involved in wheelchair or seating clinics. Pressure ulcer prevention clinics in which interface pressure is measured on a regular basis have been shown to be effective [33]. In such clinics interface pressure can be used to show the patients the effect of changing posture, such as leaning forward or to one side, to vary the distribution of pressure. The information can also be used by staff to determine the correct cushion for the individual and to determine the effects of changing the set-up of the wheelchair and cushion, such as changing the footrest height or the inflation pressure in a Roho cushion (Fig. 5.3 a, b) The illustrations in Fig. 5.3 c, d showing the effect of varying the footrest height in more detail. In fact, by changing the footrest height in 12 subjects the mean interface pressure increased twofold from 65 mmHg to 130 mmHg (from 8.7 to 17.3 kPa), whereas changing the type of cushion from the best to the worst saw an increase in interface pressure from 71 mmHg to 128 mmHg (from 9.5 to 17.1 kPa) [22]. The new pressure-measuring arrays are especially suitable for such applications. The ability to give a real-time representation of the pattern of pressure distribution on a monitor and the simplicity of using such systems in the clinical environment outweigh the disadvantages of the sensor mat affecting absolute pressure readings. What such systems do give is the ability to show the whole area of interest in a format that can be readily understood by the patients, greatly reinforcing any patient education programmes. Printouts of the pressure distribution can then be kept in the clinical records. It is not just in seating that interface pressure can be used clinically. Orthotics, in particular foot orthotics, is one area where interface pressure

62

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The Measurement of Interface Pressure

Fig. 5.3 a±b. Practical use of an interface pressure-measuring array in clinical practice

can be easily used to improve fit. Orthotic foot mats do exist for a number of the systems described above and enable the pressure-sensing surface to be placed between the customised foot orthoses and the foot to ensure that there is sufficient pressure relief over areas at greatest risk.

a

Research and Product Evaluation

z

63

Fig. 5.3 c±d. Practical use of an interface pressure-measuring array in clinical practice

Research and Product Evaluation The requirements on pressure-measuring systems in research and product evaluation are rather different than in the clinical setting. In research the absolute measurements are of greatest interest and therefore the accuracy and repeatability of the measurement is more important than the display of data, which will usually be determined by the researcher. For comparison between two or more commercial products, much greater care is needed to ensure that the measurement system and the way the results are presented do not distort

64

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The Measurement of Interface Pressure

any differences between the products. The simplest case is that of comparing two static systems. Firstly the experimental procedure has to be designed and standardised to minimise errors by controlling position and by taking multiple readings to ensure that the sensors are directly positioned under the points of interest [19±21, 23, 24, 26, 34]. In addition, falsely high readings due to creases in the sensors etc. must be avoided. Once the data have been collected the majority of researchers have used the maximum interface pressure under the area of interest as the parameter to be compared in any statistical analysis [5, 19±24, 35±39], although others have calculated an average pressure over a selected area [40]. It is noticeable that those authors who have used an average pressure find less difference between rival products. Nevertheless, even when maximum values are used, few trials report differences between product performance that are statistically significant at the 5% level. Two studies have chosen to define other parameters calculated from the data generated by multi-sensor arrays in an attempt to give an overall impression of the relative performance of different support surfaces. Patel calculated a pressure index [41] which was based on threshold levels, whereas Shelton et al. [42] calculated a pressure index based on statistical analysis. The possibility of presenting the data in different forms is far greater when dynamic systems such as alternating pressure mattresses are being considered, as by their very nature they will exert periods of high pressure followed by periods of low pressure. The most commonly quoted parameters are maximum, minimum and average pressures but these provide little indication as to the length of time that the pressure is at a lower value. This has led a number of researchers [33, 43] to report the amount of time the interface pressure is above or below a certain threshold, most conveniently displayed in histogram form. Although there is still considerable debate over what constitutes a safe interface pressure, there is, to date, no consensus. Even assuming that a suitable method can be found to analyse and present the data, all the discussion above has considered a subject in a defined posture, which is not representative of real life. In particular, individuals in a wheelchair are constantly changing their position both in the short term, as they propel themselves, and in the longer term in the course of their activities of daily living. Of the few studies to have considered this, Bar [33] produced a pressure/time histogram over a prolonged sitting period and both Dabnichki and Taktak [44] and Kernozek and Lewin [37] considered the variation of interface pressure during the wheelchair push cycle. The former study indicated that the interface pressures were speed dependent and could be increased by as much as 125% compared to the situation at rest [44].

a

Mannequins

z

65

Mannequins Design of Mannequins Measurement of interface pressure is subject to great variability. As has been shown above, there are differences among individuals and among anatomical sites, and even when the sensor is kept on a single anatomical site on a given individual, there are differences due to small changes in posture. There are also differences due to clothing, the type of measurement system used and the interpretation of the data, i.e. is the maximum or average pressure quoted or is some form of pressure index calculated? Therefore, in order to reduce this variability when comparing products designed to reduce the incidence of pressure ulcers a number of researchers have proposed using a phantom. Initially simple domed indenters were used [36], but more recently these have evolved into anthropomorphic mannequins with an internal skeleton covered by simulated soft tissues [45, 46] (Fig. 5.4). Such mannequins are the result of extensive research and their development has involved undertaking measurements on many human volunteers in order to determine the characteristics of the materials covering the skeleton. The European Pressure Ulcer Advisory Panel (EPUAP) [47] recommends the use of mannequins over human volunteers when undertaking comparative testing of products. The pros and cons of humans vs mannequins will be considered in the next section. However, the EPUAP recommendations for mannequins are that they should mimic the important degrees of freedom found in humans but also minimise the potential errors deriving from unplanned movements such as sagging or creep. Essential elements should include: 1. Full-body rather than partial mannequin. 2. Representative of typical height and weight of patients [various conditions: elderly, with spinal cord injuries (SCI) etc.] using such surfaces with weight distributed in correct anthropomorphic proportions, including a spectrum of heights/weights and male/female models. 3. Freely jointed at knees, hips, shoulders and neck, especially to allow use on a profiling bed. 4. Surface of mannequin to represent 3D shape of bony prominences and soft tissue coverage found in the patient group. 5. If different mannequins are developed in different centres then crosscorrelation data are essential. 6. It is debatable whether the mannequin needs to be heated to determine the effects on viscoelastic products in particular. 7. The mannequin needs to produce the same ranking of products as that which would be established if a large pool of human subjects were used with a given clinical condition. The use of mannequins is also recommended in the ISO draft document: ªTest methods for determining the pressure relief characteristics of devices

66

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The Measurement of Interface Pressure

Fig. 5.4. The UCL phantom designed by Bain and Scales (photograph courtesy of Centre for Disability Research and Innovation, University College London, Stanmore)

intended to manage tissue integrity ± Seat Cushionsº (ISO/CD 16840-5). In this draft document it does state that the tests described are intended to differentiate performance characteristics between cushions and are not appropriate for generalised rankings or scoring cushions or for matching these characteristics with the requirements of individual users.

Mannequins Versus Normal Volunteers Using mannequins for pressure studies has a number of obvious advantages over using human volunteers, which has led to their recommendation in the EPUAP guidelines [47]. Positioning is much more reliable as the mannequin is attached to a fixed frame and can be lowered accurately onto the support surface and sensors can be permanently attached or even imbedded in the mannequin, removing another source of error. The mannequin can also be incrementally loaded to replicate people of different

a

Mannequins Versus Normal Volunteers

z

67

Fig. 5.5. Interface pressure readings obtained on a variety of cushions using different subject groups

weight and hence different BMI and left in position for long periods of time to determine the creep behaviour of the underlying support surface. This level of control of the experimental conditions is therefore bound to reduce errors and hence show more subtle differences between products. However, the question that does have to be asked when using mannequins is `Are the readings obtained relevant to the clinical situation?' In the Department of Health Evaluation Report PS4 [23] it was clearly shown that the relative performance of the cushions tested was dependent on the underlying pathology of the different groups. One of the most interesting facts that arose from this work was that irrespective of the type of cushion the interface pressures measured on the four different groups of subjects ± elderly, CVA, spastic paraplegics and flaccid paraplegics ± were always ranked in the same order, with the elderly volunteers exhibiting the lowest pressures and the flaccid paraplegics the highest. This is demonstrated in Fig. 5.5, in which it can be seen that for the elderly subjects the choice of cushion made comparatively little difference. By contrast, in the flaccid paraplegic group there was much greater variation and therefore the choice of the cushion made far more difference to the interface pressure. In addition, it can be seen that the ranking of the products is different among the groups. In the elderly group there is little difference between the interface pressures measured on the STM4 cushions and those on the High Profile Roho. However when considering the flaccid SCI group it can be seen that the STM4 gives significantly higher pressure readings than the Roho, and in fact is only ranked as the 10th best cushion. The same is true of other cushions. The Jay Combi is ranked as the 6th best cushion for elderly volunteers, 8th for the SCI spasm group, 14th for the SCI flaccid group and 4th for the CVA group. In contrast, the Low Profile Roho is ranked 8th for

68

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the elderly group, 11th for the SCI spasm group, 3rd for the SCI flaccid group and 4th for the CVA group. What this clearly demonstrated is that there is considerable difference among groups and that any ranking based on readings obtained in one group cannot be transferred to another. Therefore a wide variety of different mannequins will be required. Perhaps one of the advantages of undertaking measurements on human volunteers is that there is this inherent variability. As a result a number of subjects have to be measured and statistical methods used in order to calculate mean values which, due to the large standard deviation, makes it difficult to separate different products. Conversely, the smaller standard deviation obtained with mannequin readings will make it much easier to differentiate between products, but only in terms of the readings obtained on the mannequin, which might not be true when applied to actual people. Therefore, it is the author's opinion that for the time being, until a variety of mannequins of different body types, weights, heights and disease states are available which have been shown to be representative of significant numbers of human volunteers, results obtained using mannequins should be viewed critically and not used in isolation to choose equipment for a given patient.

Conclusions Measuring interface pressure is difficult. As a result there is bound to be considerable debate within the scientific community as to the best way to proceed. These debates will include whether to use mannequins or human volunteers, which type of sensor array is best for clinical or research applications and how the measured interface pressure relates to interstitial pressures and in turn to the formation of pressure ulcers. There are obviously no simple answers but anyone undertaking such measurements must be aware of the limitations of present techniques: only by rigorous experimental technique will they be able to make meaningful contributions to the literature. Acknowledgements. I would like to thank all of the members of the Department of Health who have contributed to this work over the past 10 years, in particular Ellis Peters, Bill Cox Martin, Diane Norman and Wendy Wareham.

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46. Bain DS, Scales, JT, Nicholson GP (1999) A new method of assessing the mechanical properties of patient support systems (PPS) using a phantom. A preliminary report. Med Eng Phys 21:293±301 47. Support Surfaces Working Group (2002) Draft guidelines for the laboratory evaluation of pressure distributing support surfaces. European Pressure Sore Advisory Panel Review 4(1)

Susceptibility of Spinal Cord-Injured Individuals to Pressure Ulcers

6

Kath Bogie, Dan Bader

Introduction The development of pressure ulcers due to tissue breakdown and cell necrosis is one of the most significant secondary complications of spinal cord injury (SCI). There are many factors that lead to the occurrence of tissue breakdown. Similarly, SCI affects multiple systems of the body, primarily below the level of the lesion but also with systemic effect. The most readily obvious change in an individual with SCI is altered motor function, particularly that which affects limb movement. In addition, sensory dysfunction can alter proprioception and reaction to environmental stimuli such as pain and temperature. Over time, the body will change, as muscle bulk is lost due to disuse muscle atrophy, leading to a higher proportion of fatty tissue and poor vascularity. Other systems affected include cardiovascular, respiratory, bowel and bladder function, and digestion. The extent of systemic involvement and functional ability directly affects the individuals' susceptibility to development of pressure ulcers. In order to clinically describe individuals with SCI, the American Spinal Injuries Association (ASIA) has developed a standardized method for determining the neurological status of a patient and for classifying SCI. The ASIA impairment score has two components: neurological level of injury and neurological impairment. The first component describes the motor and sensory level of injury. The second describes the functional ability (Table 6.1). The ASIA impairment score is widely accepted as a clinical measure and as such it can be used as a broad indicator of a sub-population's risk for pressure ulcer development. The neurological level and extent of impairment are often very different from the anatomical level of injury, and the ASIA score provides a more reliable indicator of risk status than level of injury. Just as the ASIA impairment score contains more than one component, so the development of pressure ulcers is a multi-factorial process. These factors can be classified as extrinsic factors primarily related to the interface between the individual and external environment and intrinsic factors related to the clinical and physiological profile of the individual. Changes in clinical status following injury will alter intrinsic factors that increase the risk of tissue breakdown leading to pressure ulcer development. For example, urinary incontinence will alter the micro-environment of the skin surface and make it more susceptible to maceration and breakdown.

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Table 6.1. ASIA Impairment Score ASIA grade

Neurological function

Neurological impairment

Motor injury

Sensory injury

A

Complete

Complete

No motor or sensory function in the sacral segments S4±S5

B

Complete

Incomplete

No motor function below the level of injury. Sensory function may be normal or impaired but is present.

C

Incomplete

Incomplete

Some motor function is preserved below the level of injury but more than half the key muscles show significant weakness

D

Incomplete

Incomplete

Motor function is preserved below the level of injury and less than half the key muscles show significant weakness

E

None

None

Normal motor and sensory function

Changes in environmental factors, such as the seating system used, will alter external factors that affect pressure ulcer risk status, as summarized in Table 6.2. The interactions between risk factors and clinical status provide guidelines for susceptibility to pressure ulcer development both generally, e.g. for patient sub-groups such those with complete quadriplegia (ASIA grade A), and specifically for individuals. Intrinsic risk factors in pressure ulcer development arise as a direct consequence of the SCI. Motor paralysis below the level of a spinal cord lesion reduces muscular activity and leads to loss of muscle bulk, thus reducing soft tissue coverage over the bony prominences of the pelvic region. The proportion of avascular fatty tissue increases, leading to decreased regional vascularity. Loss of normal muscle tone leads to abnormal responses to environmental stimuli, such as applied pressure, thus increasing the risk of blood flow becoming compromised. Furthermore, individuals with higher levels of SCI are likely to experience dysfunctional central control of circulation, which can lead to autonomic dysreflexia.

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Table 6.2. Factors in pressure ulcer development Factor

Classification

Cause

Disuse muscle atrophy

Intrinsic

Motor paralysis

Reduced vascularity and blood flow

Intrinsic

Motor paralysis

Impaired/absent sensation

Intrinsic

Sensory paralysis

Reduced mobility (including loss)

Intrinsic

Motor paralysis

Poor nutritional status

Intrinsic

Poor diet

Applied pressure

Extrinsic

External loading of soft tissues

Shear at the support interface

Extrinsic

Poor posture and/or poor support materials

Adverse micro-environment at support interface

Extrinsic

Numerous, including raised temperature, sweating, incontinence, infection

Motor paralysis will also directly affect a person's ability to respond unconsciously to potential noxious stimuli, e.g. fidgeting while sitting or turning while asleep. Reduced mobility also profoundly alters the individual's ability to consciously perform postural manoeuvres necessary to relieve prolonged applied pressure, from weight-shifting while sitting to walking. The loss or reduction of mobility is further compromised by sensory paralysis, leading to the absence or alteration of normal perception of environmental stimuli such as pain or temperature. Individuals with complete sensory paralysis can no longer sense where their limbs are without visual cues, i.e. they experience a loss of proprioception. These changes affect the risk of pressure ulcer development because the individual cannot sense the warning signals that prompt action to prevent tissue damage. Thus it can be seen that many of the primary factors that increase the susceptibility of individuals with SCI to pressure ulcer development are the inter-related intrinsic changes in body characteristics and functional abilities which occur following SCI. To a large extent, these changes have been considered to be immutable. Nutritional status can be altered by adequate diet, but a complete SCI remains an irreversible lesion that does not exhibit spontaneous recovery. There is much research currently in progress to develop clinical treatments to cure SCI. This remains exploratory, and thus the current clinically applicable techniques to prevent pressure ulcers largely address extrinsic factors that can be changed, such as applied pressure and the micro-environment of the user/support interface. These approaches to pressure ulcer prevention can be classified as education focused or device focused. Educational prevention techniques include programmes that address patient and/or carer education. Device-oriented methods focus on

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the provision of appropriate equipment for postural support and pressure relief, such as mattresses and wheelchair seating cushions. These approaches to pressure ulcer prevention are complementary and should be reviewed periodically throughout the lifetime of the individual with SCI.

Variation in Pressure Ulcer Risk Factors Following SCI The clinical profile of an individual with an SCI will vary both among individuals, due to different levels of lesion, and for one person over time. The individual with an SCI will undergo the ageing process with chronic motor and/or sensory dysfunction. Moreover, it has been shown that an SCI can increase the effective rate of ageing [1, 2]. As more people live longer with SCI, research has been carried out to determine the longer-term risk status for clinical complications. With specific regard to the risk of pressure ulcer development, the individual with SCI remains at increased risk at all times post injury; however, the relative risk status and the most critical risk factors will vary over the course of time. The first stage at which pressure ulcer risk is heightened is in the acute SCI phase, immediately following injury.

Risk Factors During SCI Following traumatic injury to the spinal cord there is an immediate decrease or loss of reflex activity below the level of the lesion. This condition is known as `spinal shock' and although it is transient, there is considerable variation in the period required for the restoration of this activity, ranging from a few days to several months. Reflex return may be particularly delayed in patients with severe but incomplete SCI [3]. In addition, there is frequently concurrent trauma to multiple systems, which must be addressed with urgency if the patient is to survive the initial insult. Thus, the treatment received in the period immediately following a traumatic SCI is critical both to initially stabilize the patient and to ensure an optimal prognosis once the acute phase is past. It is important that skin care is rigorously monitored, for the development of pressure ulcers during the immediate post-injury phase will severely impede subsequent rehabilitation. Patients who sustain an SCI should be admitted as soon as possible to a specialized spinal injuries unit, because secondary complications will start very rapidly following SCI. Even among specialized units, the standards of care for acute SCI vary from conservative treatment to rapid spinal stabilization and remobilization. The original protocol pioneered by Guttmann takes a very conservative approach [4]. The patient is immobilized for up to 12 weeks, to allow the traumatic fracture to stabilize, before gradually commencing a rehabilitation programme. Tissue health status should continue to be monitored to avoid development of pressure ulcers. In addition to prolonging the acute phase of the hospital admission, the early develop-

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Table 6.3. Demographics of acute SCI study population Gender

Age

Level of injury

Extent of injury

Male: 73%

16±32 years

Above T6: 33%

Complete: 40%

Female: 27%

Mean: 22 years

Below T6: 67%

Incomplete: 60%

ment of pressure ulcers can negatively affect the individual's psychological adjustment to life with an SCI. The pressure-relieving characteristics of the user support surfaces, at this stage specifically the mattress and any other support pillows, should therefore be evaluated together with the positioning of the individual in the bed. Conservative management of acute SCI, such as employed at the National Spinal Injuries Centre, Stoke Mandeville NIH Trust, is for the patient to be immobilized until the fracture is stable, as seen on radiographic assessment of the site. The patient is positioned in a supine position with the spine in alignment and lies on a foam mattress with pillows placed under the head, buttocks and ankles to relieve pressure on the high-risk pressure points of the occiput, sacrum and heels. A turning regime is employed where the patient is turned from side to side using a turning bed at 2- to 4-h intervals, with the spine maintained in alignment at all times. A study was carried out to evaluate the efficacy of this clinical treatment protocol for maintenance of tissue health. Interface pressures and transcutaneous oxygen levels were measured at the sacrum of subjects who had sustained a traumatic SCI [5]. Fifteen individuals were admitted to the study within 9 weeks of injury. The clinical demographics of the study population are summarized in Table 6.3. Transcutaneous oxygen levels were measured using a Radiometer TCM3 blood gas monitor (Copenhagen, Denmark). The sensor electrode was placed over the sacrum along the midline. Concurrently, interface pressures were measured on either side of the tissue gas electrode using an Oxford Pressure Monitoring system (Talley Medical, Romsey, Hants, UK). Measurements were made for a period of 25Ô5 min at intervals of 1±2 weeks until the subject began to remobilize in a wheelchair. It was found that median interface pressures at the sacral region were around 30 mmHg. This implies that the practice of ªgappingº patients on pillows to relieve pressures over the bony prominences is often ineffective because an adequate gap is not achieved. The simplest approach to remedy this situation is to employ clinical guidelines that indicate the minimum gap necessary around a bony region. This would generally be around 10 cm, but this may not always be feasible if there is significant spinal instability, and in such cases it would be more effective to use an active pressure relief mattress, such as a Clinitron bed, (Hill-Rom, Ashby de la Zouch, Leicestershire).

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No significant relationship between transcutaneous oxygen level and time post injury was found, indicating that the risk of tissue breakdown did not alter during the period of acute immobilization for this subject group. This implies that rapid remobilization and reduced frequency of turning when in bed may be inappropriate for many individuals with acute SCI due to the prolonged effects of spinal shock. As the proportion of cases of incomplete spinal cord trauma increases and acute bed rest continues to become briefer, this has significant implications for the clinical care of acute SCI patients.

Risk Factors During Initial Rehabilitation The initial rehabilitation (sub-acute) phase for an individual with SCI can vary in both time post injury (from a few weeks to several months), depending on the course of the acute phase, and duration (also from a few weeks to several months). The goal of initial rehabilitation post SCI is to equip the individual with the skills and equipment necessary for them to maximize their potential abilities so that they can become reintegrated in society. This goal requires much hard work by the affected individual, his or her caregivers and the whole clinical team. It is of primary importance that during initial rehabilitation every patient and carer is thoroughly educated in the aetiology of pressure ulcers and their prophylaxis. Critical skills to be learned include the ability to carry out a pressure relief regime, both through postural changes where possible and through the provision of appropriate equipment, e.g. cushions, wheelchairs, mattresses. The need for routine skin inspection and care must also be emphasized, with particular regard to pressure areas such as the ischia, sacrum and greater trochanters. The selection of a wheelchair seating system for the person who has recently sustained an SCI must involve consideration of many diverse criteria. In some ways it is the most important part of rehabilitation. The right combination of wheelchair and support cushion will allow the user to maximize their functional potential and interact fully with their environment. In addition, it will take full account of the user's requirements with regard to particular needs and appearance. Conversely, an inappropriate seating system can lead to poor posture, reduced functional abilities and isolate the user from their environment. All these factors can, in turn, exacerbate the risk of pressure ulcer development in the rehabilitating individual. Thus the seating requirements of each patient must be thoroughly assessed at this time so that appropriate seating and other support surfaces can be recommended. The prescription of wheelchair seating systems must be based on a comprehensive assessment of user function (actual and potential) and seated posture. The clinical profile should be considered but of greater relevance are the actual individual characteristics at the seating/ support interface for a specific user. A study was carried out to determine changes in transcutaneous oxygen response to applied pressure during the initial rehabilitation of SCI sub-

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jects [6]. All study participants had suffered traumatic SCI less than 1 year previously and were assessed while sitting on their prescribed support cushions. The initial guidelines for cushion prescription were for all patients to receive a 4-in. foam cushion, except those with complete quadriplegia who more frequently received a Sumed gel cushion. Subjects with a history of pressure ulcer development during the acute phase were prescribed a Jay Medical or Jay Active foam/gel cushion. Subjects were classified according to their level of injury as paraplegic (below T6) or quadriplegic (above T6). Transcutaneous oxygen levels were measured over the bony prominence of the ischial tuberosity using a Radiometer TCM3 blood gas monitor. Initial assessment was made once the patient was sitting up for more than 4 h a day and was repeated at intervals of 2±4 weeks until discharge. The sensors were attached with the subject in a side-lying position with hips and knees flexed to approximate their relative posture in sitting. After a 10-min equilibration period the subject was carefully transferred to the sitting posture on their support cushion. Tissue status was then monitored for a continuous period of 25Ô5 min with appropriate pressure relief as required. Tissue oxygen levels under applied load tended to improve during initial rehabilitation for quadriplegic subjects and to deteriorate for those with paraplegia. These counter-intuitive findings support the reports of others, such as Noble [7], that quadriplegics develop pressure ulcers less frequently than paraplegics, particularly than those with flaccid paraplegia. This may be because the spasticity experienced by individuals with higher level lesions means that loss of muscle bulk is slightly less than in those with no tone, i.e. with flaccid paralysis. The higher activity levels of paraplegic individuals may also be a factor since they may be more likely to neglect regular pressure relief manoeuvres due to their other activities.

Risk Factors for the Chronic SCI Population Following initial rehabilitation, the SCI patient must maintain a high level of skin care at all times in order to prevent the occurrence of pressure ulcers. However, this economically and psychologically costly secondary complication remains one of the most common reasons for re-admission to hospital [7]. The patient with a major pressure ulcer requires an average of 180 days nursing time [8]. Allman et al. [9] found that development of a nosocomial pressure ulcer was associated with significant and substantial increases in both hospital costs and length of stay in a group of patients admitted to hospital with reduced mobility due to a primary diagnosis of hip fracture. Xakellis and Frantz [10] found that the cost of treating pressure ulcers was greatly increased when a patient required hospitalization. These studies did not focus on individuals with SCI, but it can reasonably be predicted that the outcomes would be poorer for those individuals with greater initial impairment. The most recent comprehensive figures available

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indicate that the cost to the health service in the UK is in excess of £ 250 million per annum in 1990 [11]. In the USA, the cost of treating pressure ulcers was estimated to be in excess of $ 1.33 billion per annum in 1994 [12]. When adjusted for inflation, this implies that current costs are around £ 416 million per annum in the UK and around $ 1.89 billion per annum in the USA. Thus it can be seen that the prevention of pressure ulcers is a highly cost-effective goal. Pragmatically, it is also important to have clear treatment guidelines for the efficacious clinical management of pressure ulcers when they do develop. Both the European Pressure Ulcer Advisory Panel (EPUAP) and the National Pressure Ulcer Advisory Panel (NPUAP) have issued clinical guidelines for the prevention and treatment of pressure ulcers [13, 14, 15]. It is recommended that conservative treatment options, such as topical dressings, be employed whenever possible for the individual with chronic SCI who develops a pressure ulcer. In most cases early identification of a Grade I or II pressure ulcer with superficial breakdown involving only the dermal layers can be treated successfully by complete bed rest with total pressure relief over the affected area combined with appropriate dressings, as the healing period is relatively short. There are many types of topical dressings and antibiotics that can be employed to promote wound healing [12]. The common goal is to produce a moist wound environment that will promote cell proliferation. In some cases, tissue breakdown is so extensive that conservative treatment alone is not appropriate. Grade III or IV pressure ulcers involve total breakdown of the dermal and epidermal layers, sometimes extending to the underlying muscle, that requires a prolonged period of bedrest to heal. This cannot be considered acceptable. The presence of necrotic tissue (eschar) will impede wound healing and such tissue may be removed by surgical intervention, specifically sharp debridement. Excision of sloughy tissue and cleansing of the ulcer to stop infection should permit the development of granulating tissue. Split skin grafts may be employed to promote healing in the early stages for pressure ulcers with limited muscular involvement. However if the pressure ulcer exhibits areas of deep tissue breakdown, e.g. extending to the bone with surrounding undermining and fibrotic margins (Grade IV and some Grade III ulcers), more radical surgical treatment is required. The overall goal of surgical procedures is to excise and close the ulcer. A number of tissue-flap procedures have been developed to achieve wound coverage. Myocutaneous flaps and island fasciocutaneous flaps are most widely used [16, 17], with fasciocutaneous flaps also being found to be successful on some non-healing pressure ulcers [18]. The principal procedure employed at the National Spinal Injuries Centre is simple excision of the ulcer and bony prominence followed by direct closure. The ulcer is excised in toto with the bony prominence underneath. The wound is then closed in layers with a primary skin closure. A retrospective review of surgical patients with pressure ulcers treated at the National Spinal Injuries Centre by excision and closure was carried out. All

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patients admitted during a twelve year period (1980±1992) and treated by the same surgeon (IN) were studied and evaluated. A total of 400 operational procedures involving 218 patients were performed. There was a 2.25% incidence of multiple ulcers, leading to an overall total of 409 ulcers repaired surgically over the twelve year period. The retrospective review of surgical cases showed that some patients experienced more than one surgical procedure during the period. It was important to differentiate between possible causes of repeated tissue breakdown and therefore two classes of repeated procedure were defined. Revision of a pressure ulcer was defined as a repeated surgical procedure at the same site within 1 year of the original procedure. This was considered to indicate that the original wound had failed to heal adequately. In contrast, recurrence of tissue breakdown was defined as a surgical procedure at the same site between 1 and 5 years after the original procedure. During the 12-year review period 73 patients (33.5%) were treated on two or more occasions. In 37 of these cases this was due to bilateral and/or multiple ulcers being repaired by a series of surgical procedures. Surgical revision was found to have been required in 24 cases (6.0%). Recurrence of tissue breakdown was found to have occurred in 15 cases. One patient had two episodes of tissue breakdown at the same site 3 and 6 years after initial surgery. One other patient had recurrent breakdown over bilateral trochanteric regions after a 4.5-year interval. Thus a total of 18 ulcers (4.5%) recurred during the 12-year review period. The relative prevalence of the 409 pressure ulcers treated by surgical excision and closure is summarized in Table 6.4, together with revision and recurrence rates. When these cases were classified according to the site of the initial pressure ulcer, revision rates appeared to be higher for the sacrum and greater trochanter than for the ischium. The reverse situation was seen with recurrence rates. Ischial ulcers were twice as likely to exhibit repeated breakdown requiring surgical repair as those occurring at the sacrum or greater trochanter. Twenty-one (9.6%) patients had two or more episodes of tissue breakdown at different sites separated by periods greater than 1 year, e.g. initial breakdown of the ischial region with a second breakdown of the sacral region 4 years later. However, it was noted that 10 of these patients also had a history of concurrent multiple pressure ulcers at some time during the

Table 6.4. Revision and recurrence rates classified by pressure ulcer site Pressure ulcer site

Revisions

Recurrences

Sacrum

7 (7.0%)

3 (3.0%)

Ischium

9 (5.5%)

10 (6.1%)

Greater trochanter

8 (6.6%)

4 (3.3%)

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review period. Seven patients had a history of recurrent ischial ulcers where the left or right side was specified for all ulcers. In these cases, recurrent breakdown was contralateral in four patients and on the same side in two patients. One patient exhibited recurrent ischial breakdown both contralaterally and ipsilaterally. This finding implies that prophylactic ischiectomies may be effective at preventing recurrent breakdown over the same ischial tuberosity but they may increase the risk of contralateral breakdown due to postural asymmetry. In this review we were able to assess the operational procedures by one surgeon over a 12-year period from 1980 to 1992, thus providing longer-term follow-up information. The recurrence rate of 5.3% for all ulcers represents an overall success rate of 94.7%, with 5 years' follow-up, for sacral, ischial and trochanteric ulcers closed by direct excision and closure. This compares favourably to other surgical techniques for the repair of pressure ulcers. A prospective study was carried out to evaluate any changes in transcutaneous gas levels pre-operatively and to determine whether tissue health status is altered in unloaded and loaded soft tissues post-operatively. Transcutaneous gas levels were monitored in subjects who underwent surgical excision and closure of pressure ulcers during the period June 1989 to December 1990. Ethical approval for this study was obtained from the Aylesbury Vale Authority Research Ethical Committee. Twenty-one subjects were included in this study on meeting the selection criteria, i.e. normal haemoglobin levels pre-operatively, absence of systemic degenerative conditions and provision of informed consent. Three cases in this group had bilateral ulcers, leading to a total of 24 ulcers. The clinical demographics of this study population are shown in Table 6.5. Tissue health was assessed pre-operatively once the area of tissue breakdown was free of slough and necrotic tissue. The sensor electrode of the Radiometer TCM3 blood gas monitor was located 20±50 mm from the margin of the wound over superficially healthy skin. Transcutaneous gas levels were monitored for a period of 25Ô5 min in order to determine a stable unloaded tissue response. The pressure ulcer was then repaired by total excision of the necrotic tissue, ulcer and underlying bony prominence followed by primary closure. An elliptical incision was made around the ulcer, followed by excision of the Table 6.5. Clinical demographics of surgical study population: summary of subject profiles Gender

Age

Level of injury

Duration of injury

Location of ulcer(s)

Male: 76%

16±80 yrs

Above T6: 33%

Acute: 14%

Ischium = 58%

Female: 24%

Mean: 42 years

Below T6: 67%

Chronic: 86%

Sacrum = 13% Trochanters = 29%

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whole ulcer, making sure that the pseudo-epithelial lining of the ulcer was excised in toto. The underlying bony prominence was exposed and excised. In ulcers with undermined cavities, the boundaries of the cavity are easily identified by packing it with ribbon gauze and thus changing it into a pseudotumour. Dissection was then carried out to remove the whole lining. Table 6.6. Clinical demographics of surgical study population: individual subject profiles Gender

Age

Level

Duration a

Location of ulcers

Previous surgical repair

1

M

50

A

Chronic

R ischium

N

2

M

27

B

Chronic

L ischium

N

3

M

42

B

Chronic

Sacrum

N

4

F

80

A

Chronic

L ischium

Y

5

M

59

A

Chronic

R ischium

Y

6

M

43

A

Acute

Sacrum

N

7

M

19

A

Chronic

L posterior trochanter

N

8

F

71

B

Chronic

L ischium

N

9

M

57

B

Chronic

R ischium

N

10

M

37

A

Chronic

B. posterior trochanters

N

11

M

19

B

Chronic

L ischium

Y b, c

12

F

36

B

Chronic

L ischium

N

13

F

22

B

Chronic

Bilateral ischia

±c

14

F

22

B

Chronic

R ischium and perineum

±c

15

M

16

B

Acute

Bilateral trochanters

N

16

M

38

B

Chronic

L posterior trochanter

N

17

M

19

B

Acute

Sacrum

N

18

M

50

B

Chronic

R ischium

N

19

M

72

A

Chronic

L trochanter

N

20

M

43

B

Chronic

L ischium

Yb

21

M

58

B

Chronic

L ischium

N

No.

a b c

Acute, less than 2 years post-injury; Chronic, more than 2 years post-injury. Previously repaired by rotation flap. Full surgical history not available.

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The wound was then closed in as many layers as possible. This makes closure of the ulcer achievable without undue tension. A suction drain was always left for a few days in order to drain the deep area. The sutures were usually removed in two stages at 10 and 11 days postoperatively. Twenty-four hours following removal of all sutures, transcutaneous gas levels in unloaded tissues were again assessed. The monitoring site was 20±50 mm medial to the mid-point of the suture line. A further assessment of tissue response under load was carried out following remobilization in the wheelchair for 19 subjects. Transcutaneous gas levels were monitored at the same site as for the post-operative assessment. Regional interface pressures at the subject support interface were monitored simultaneously using the Oxford Pressure Monitoring system. The sensors were located using the same experimental protocol followed for the study of initially rehabilitating SCI subjects (see above). Sensors were attached over the region of the surgical repair with the subject in a side-lying position with hips and knees flexed to approximate their relative posture in sitting. The tissue gas electrode was located 20±50 mm medial to the mid-point of the suture line and the pressure sensors were placed either side. After a 10-min equilibration period the subject was carefully transferred to the sitting posture on their standard support cushion. Tissue status was then monitored for a continuous period of 25Ô5 min with the appropriate pressure relief as required. The distribution of pressure ulcer locations found in the long-term review was reflected in the study of transcutaneous gas levels in surgical subjects, with ischial ulcers representing 58% of cases. The unloaded transcutaneous oxygen pressure (TcPO2) in normal healthy subjects is considered to be in the region of 80 mmHg [19]. The risk of tissue necrosis increases as the blood supply becomes inadequate and TcPO2 falls. Unloaded TcPCO2 is around 35 mmHg. If tissue health becomes compromised due to inadequate blood supply, TcPCO2 will start to increase due to the accumulation of noxious by-products from tissue respiration. Pre-operatively, TcPO2 was generally found to be in excess of 30 mmHg, and TcPCO2 levels were abnormally high in a number of cases. Thus soft tissues surrounding regions of necrotic tissue may have slightly compromised tissue gas levels due to a reduced clearance of tissue waste, even though they may appear visually normal. Post-operatively TcPO2 levels in unloaded tissues were generally observed to be in excess of 30 mmHg and TcPCO2 was within the normal range for an increased number of subjects. Thus transcutaneous gas levels in unloaded tissue surrounding a repaired wound were similar to those found in other healthy soft tissues. This may be due to the operation itself stimulating blood flow, or it may simply be that regional blood flow improves as a result of the removal of necrotic tissue.

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Future Developments in Pressure Ulcer Research

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Future Developments in Pressure Ulcer Research: Decrease in the Susceptibility of the Individual with SCI Despite the development of many support devices and the application of many training programs the incidence of pressure ulcers remains unacceptably high, particularly in the SCI population. Furthermore, there remain a significant number of individuals with SCI who exhibit chronic recurrence of tissue breakdown despite the use of high-performance support cushions. Device-orientated prevention techniques continue to be developed and refined. Active pressure-relief mattresses often incorporate temperature sensors to control the micro-environment, and this type of technology is now starting to be applied in wheelchair cushions. In addition, `smart' cushions have been developed that monitor the duration of applied pressure, i.e. static sitting time, and issue an alarm when the user should perform a pressure-relief manoeuvre. Advanced technologies and new pharmacological approaches are being explored that can affect the intrinsic clinical status of the individual with a SCI. The long-term application of implanted electrical stimulation devices offers a unique means to alter the intrinsic characteristics of paralysed muscle, leading to sustained improvements in regional tissue health. These changes can reduce the risk of pressure ulcer development by increasing regional blood flow and improving interface pressure distribution [20]. In addition, electrical stimulation can be applied to dynamically alter conditions at the seating support interface through stimulated muscular contractions, thus facilitating periodic changes in interface pressure. The use of anabolic steroids has also been investigated for both the treatment and prevention of pressure ulcers in the SCI population. Any individuals with chronic `non-healing' pressure ulcers exhibit concurrent malnutrition and weight loss. The anabolic steroid, oxandrolone, has been found to be effective on pilot studies of wound treatment. A significant majority of individuals exhibited healing of pressure ulcers after treatment for up to 6 months [21, 22]. Demling and De Santi found that optimizing nutrition alone was ineffective. However, when this was supplemented with oxandrolone therapy there was an increase in weight gain by around 1.8 kg/week (4 lb/week), which was significantly correlated with wound closure. Weight gain due to oxandrolone is primarily lean body mass, i.e. muscle tissue. No side effects have been noted with oxandrolone and this approach may therefore be applicable for pressure ulcer prevention in malnourished individuals at high risk for pressure ulcer development. Further study is necessary to determine the safety and efficacy of oxandrolone for long-term therapy. In addition to altering the intrinsic susceptibility of individuals with SCI the incidence of pressure ulcers may be decreased by more effective delivery of care. Current clinical management is predominantly based on the ethos that pressure ulcers are avoidable given adequate preventative care, and the fact that they continue to occur at high rates is seen to imply that

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the patient is to some degree negligent. However, the validity of the underlying assumptions of this care model warrants further investigation. Adequate preventative care implies that individuals at risk of pressure ulcer development are receiving both appropriate education and appropriate equipment. A recent survey of the prevalence of pressure ulcers in 5,000 hospitalized patients throughout Europe, carried out by the EPUAP, indicates that the first criterion is frequently not met [23]. The survey included all hospital inpatients, and it could be argued that individuals with SCI are not typical and will receive adequate prophylactic care. On the other hand, it can be seen from the studies presented in this paper that clinical expertise and standard treatment guidelines are not in themselves sufficient. They should be considered the starting point for effective prevention of pressure ulcers, rather than the end point. The majority of specialized SCI rehabilitation units will provide educational programs for in-patients with acute SCI or when people are re-admitted for continuing care. However, the fact that an individual requires inpatient hospital care for treatment of a complication such as a pressure ulcer generally implies a failure in the educational process, since the problem has not been managed at an early stage. The incongruity is illustrated by the findings of a recent survey by Walter et al. [24], who found that 38% of participants reported having current problems with a pressure ulcer but only 21% of these individuals wanted to discuss their problem with a therapist. A satisfaction rate of around 80% among this group would appear somewhat unexpected. Various approaches to improving educational awareness have been proposed. Some are based on refining the existing models of care through the development of more accurate scales for predicting pressure ulcers [25]. Others seek to modify the model through the incorporation of new technology and increased patient involvement with their care. Initial studies have shown that the use of telehealth interventions may improve the tracking and management of pressure ulcers [26]. It was found that video monitoring combined with access to a telephone helpline will increase the number of reported pressure ulcers. However, the majority of this increased incidence is due to the reporting of Grade I and II pressure ulcers that are rarely reported in standard care models. Thus, the telehealth intervention produced an increased rate of health care utilization but this was generally to deal with less severe complications and could therefore be more cost effective. It was also found that people who employed telehealth were more likely to return to work. This has led to the hypothesis that telehealth may promote self-efficacy among users with SCI. Future work is required to investigate the role of telehealth on both physiological and psychological variables affecting the risk of SCI individuals for pressure ulcer development. Changing the medical model to include the patient in his or her own care is another component in the future development of approaches to decreasing susceptibility to pressure ulcer development. Contingency management is a behavioural methodology that has been widely used in the treatment of substance abuse. The general protocol is reinforcement of positive patterns of be-

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haviour through a reward system, such as financial compensation or vouchers, with the overall objective of the individual internalizing the behaviour patterns so that they no longer need the rewards in order to carry them out. Contingency management procedures have been designed for patients with high rates of non-compliance in skin care [27]; however, there is some controversy over the use of monetary rewards [28]. Further work is necessary to determine the long-term efficacy of this approach to behavioural modification. Even as the incidence of and prognosis for SCI changes with improved prevention and the possibility for a cure, so the susceptibility to pressure ulcer development in the current SCI population is changing with new developments in many fields. Behavioural techniques and technological developments can alter the risk status of individuals by changing environmental factors. Implanted technologies and pharmacological agents have the potential to alter clinical risk factors, in particular by reversal of disuse muscle atrophy. The development of these multi-factorial preventative approaches expands the possibilities for reducing the future incidence of pressure ulcers in the spinal cord-injured population.

References 1. Charlifue SW, Weitzenkamp DA, Whiteneck GG (1999) Longitudinal outcomes in spinal cord injury: aging, secondary conditions, and well-being. Arch Phys Med Rehabil 80(11):1429±1434 2. Thompson L (1999) Functional changes in persons aging with spinal cord injury. Assist Technol 11(2):123±129 3. Little JW, Ditunno JF, Stiens SA, Harris RM (1999) Incomplete spinal cord injury: neuronal mechanisms of motor recovery and hyperreflexia. Arch Phys Med Rehabil 80:587±599 4. Guttmann L, Cope Z (eds) (1953) The treatment and rehabilitation of patients with injuries of the spinal cord. Her Majesty's Stationery Office, London 5. Bogie KM, Nuseibeh I, Bader DL (1992) Transcutaneous gas tensions in the sacrum during the acute phase of spinal cord injury. Proc Instn Mech Engrs 206:1±6 6. Bogie KM, Nuseibeh I., Bader DL (1995) Early progressive changes in the seated spinal cord injured subject. Paraplegia 33:141±147 7. Noble PC (1981) The prevention of pressure sores in persons with spinal cord injuries. In: Monograph 11, International Exchange of Information in Rehabilitation. Rehabilitation Fund Inc., New York 8. Hibbs P (1990) The economics of pressure sore prevention. In: Bader DL (ed) Pressure sores ± clinical practice and scientific approach. Macmillan Press, London, pp 35±42 9. Allman RM, Goode PS, Burst N, Bartolucci AA, Thomas DR (1999) Pressure ulcers, hospital complications, and disease severity: impact on hospital costs and length of stay. Adv Wound Care 12(1):22±30 10. Xakellis GC, Frantz R (1996) The cost of healing pressure ulcers across multiple health care settings. Adv Wound Care 9(6):18±22 11. Cochrane G (1990) The severely disabled. In: Bader DL (ed) Pressure sores ± clinical practice and scientific approach. Macmillan Press, London, pp 81±96

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12. Bergstrom N, Bennett MA, Carlson CE, et al. (1994) Treatment of pressure ulcers. Clinical practice guideline No. 15. US Department of Health and Human Services, Agency for Health Care Policy and Research. Rockville MD. AHCPR publication No. 95-0652 13. European Pressure Ulcer Advisory Panel (1998) Guidelines on prevention of pressure ulcers. Br J Nurs 7:888±889 14. European Pressure Ulcer Advisory Panel (1999) Guidelines on treatment of pressure ulcers. EPUAP review 1:31±33 15. Garber SL et al. (2000) Consortium for Spinal Cord Medicine, Pressure ulcer prevention and treatment following spinal cord injury: a clinical practice guideline for health-care professionals. Paralyzed Veterans of America, NPUAP 2000 clinical guidelines 16. Lee HB, Kim S, Lew D, Shin K (1997) Unilateral multilayered musculocutaneous flap for the treatment of pressure ulcer. Plast Reconstr Surg 100(5):340±345 17. Erocan AR, Apaydin I, Emiroglu M et al. (1998) Island VY tensor fascia lata fasciocutaneous flap coverage of trochanteric pressure ulcers. Plast Reconstr Surg 102(5):1524-1531 18. Yamamoto Y, Tsutsmida A, Murazumi M, Sugihara T (1997) Long-term outcomes of pressure ulcers treated with flap coverage Plast Reconstr Surg 100(5):1212±1217 19. Bennett L, Kavner D, Lee BY, Trainor FS, Lewis JM (1984) Skin stress and blood flow in sitting paraplegic patients. Arch Phys Med Rehab 65:186±190 20. Bogie KM, Reger SI, Levine SP (2000) Therapeutic applications of electrical stimulation: wound healing and pressure sore prevention. Assistive Technol 12(1):50±66 21. Spungen AM, Koehler KM, Modeste-Duncan R, Rasul M, Cytryn AS, Bauman WA (2001) Nine clinical cases of nonhealing pressure ulcers in patients with spinal cord injury treated with an anabolic agent: a therapeutic trial. Adv Skin Wound Care 14(3):139±144 22. Demling R, De Santi L (1998) Closure of the ªnon-healing woundº corresponds with correction of weight loss using the anabolic agent oxandrolone. Ostomy Wound Manage 44(10):58±62, 64, 66 passim 23. European Pressure Ulcer Advisory Panel (2001) The prevalence of pressure ulcers in European hospitals [online publication]. EPUAP Review 3, 2001: available online at: http://www.epuap.org/review3_3/index.html 24. Walter JS, Sacks J, Othman R, Rankin AZ, Nemchausky B, Chintam R, Wheeler JS (2002) A database of self-reported secondary medical problems among VA spinal cord injury patients: its role in clinical care and management. J Rehabil Res Dev 39(1):53±61 25. Salzberg CA, Byrne DW, Cayten CG, Kabir R, van Niewerburgh P, Viehbeck M, Long H, Jones EC (1998) Predicting and preventing pressure ulcers in adults with paralysis. Adv Wound Care 11(5):237±246 26. Phillips VL, Temkin A, Vesmarovich S, Burns R, Idleman L (1999) Using telehealth interventions to prevent pressure ulcers in newly injured spinal cord injury patients post-discharge. Results from a pilot study. Int J Technol Assess Health Care 15(4):749±755 27. Mathewson C, Adkins VK, Jones ML (2000) Initial experiences with telerehabilitation and contingency management programs for the prevention and management of pressure ulceration in patients with spinal cord injuries. J Wound Ostomy Continence Nurs 27(5):269±277 28. Adkins VK, Mathewson C, Ayllon T, Jones M (1999) The ethics of using contingency management to reduce pressure ulcers: data from an exploratory study. Ostomy Wound Manage 45(3):56±58, 60±61

Prevention and Treatment of Pressure Ulcers Using Electrical Stimulation

7

Thomas Janssen, Christof Smit, Maria Hopman

Introduction Skin-related secondary disabilities, especially pressure ulcers, are a common problem for wheelchair users such as individuals with spinal cord injury (SCI), resulting in great discomfort and significant medical care costs. Pressure ulcers typically arise in areas of the body where prolonged pressure and shear forces are being exerted on soft tissue over bony prominences, such as the sacrum and the ischial tuberosities, inhibiting blood and oxygen supply and ultimately causing tissue ischaemia and necrosis. Individuals with SCI are at increased risk for pressure ulcers due to factors such as reduced mobility, reduced microcirculation, impaired sympathetic function, atrophy of the paralysed muscles, and a disturbed muscle pump function (also see Chap. 6). In addition, due to impaired sensation, individuals are often not aware of the necessity to relieve pressure. Although it has been shown that special cushioning systems can provide an improved redistribution of pressure, as has been reviewed in Chaps. 5 and 6, pressure ulcers still are prevalent in the SCI population. The predisposition of SCI patients with flaccid paralysis to ulcer development has been outlined in Chap. 5. It is theoretically possible that electrical stimulation (ES) and ESinduced exercise can help to reduce the risk of pressure ulcers, since they have been shown to increase muscle mass, capillary density and skin and muscle blood flow (BF). The first purpose of this chapter, therefore, is to discuss how ES can contribute to reduction of pressure ulcer risk and pressure ulcer incidence. The second purpose is to evaluate how ES can be helpful in pressure ulcer healing once preventative measures have failed.

Electrical Stimulation Technique It is beyond the scope of this chapter to give a complete overview of ES techniques, application principles, precautions and contra-indications. In this chapter we will review briefly the general techniques of ES to induce muscle contractions and increase BF. For a more comprehensive review of

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ES methodology, the reader is referred to, for example, Robinson and Snyder-Mackler [1]. The basic technique to induce muscle contractions for exercise via ES involves the use of an electrical stimulator providing impulses to skin surface electrodes placed over the muscle to simulate action potentials that would normally arise from the central nervous system. These impulses evoke action potentials in the motor neurons entering the muscle. The action potentials subsequently activate the neuromuscular junctions to release acetylcholine, evoking action potentials in all of the muscle fibres of the motor units (i.e. motor neurons and the skeletal muscle fibres they innervate), and thereby inducing muscle contractions. Thus, it is desirable to place electrodes directly over motor points, i.e. where the motor nerve enters the muscle, to obtain optimal muscle performance at relatively low ES current. Impulses are typically delivered at a frequency of 30±50 Hz to induce smooth, tetanic contractions. Contraction strength can be varied by adjusting the ES current intensity, since this directly relates (within limits) to the number of motor units activated. During a period of exercise, the muscle fibres undergo progressive fatigue and their force output decreases. To compensate for fatigue, ES current intensity must be progressively increased during the exercise period to recruit fresh, non-fatigued muscle fibres. This protocol is automatically accomplished in advanced ES systems via performance feedback circuitry. However, once the maximal current output intensity of the stimulator is reached, muscle performance will markedly decrease and become insufficient to maintain required levels of exercise. The rate of fatigue for ES-induced contractions is most likely higher than for voluntary contractions due to the non-physiological activation technique, histochemical changes in the weakened paralysed muscle fibres and reduced circulation of blood [2].

ES Modes The two most commonly used ES-induced exercise modes in individuals with SCI are resistance exercise and endurance exercise. Research has demonstrated that the same resistance-training principles known to be effective for strengthening and inducing hypertrophy of the muscles of able-bodied individuals with voluntary exercise can be applied to ES-induced exercise of paralysed muscles. These principles include isometric contractions, as well as dynamic concentric and eccentric contractions through a safe range of joint motion, progressive ªoverloadº, several sets of exercise consisting of a relatively low number of repetitions at relatively high load resistance, and two to five sessions of exercise per week [3±6]. Most research on ES resistance exercise has been directed towards the paralysed quadriceps muscles due to their responsiveness to ES, proportional increase in force output with increasing ES current and relative ease of exercise implementation. However, it is probable that this ES technique can be adapted to provide resistance exercise for other paralysed/weakened muscles. For endurance exercise, a leg cycle ergometer (LCE) was developed in 1982 which is

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Fig. 7.1. Illustration of an individual with SCI on a commercially available leg cycle ergometer that uses electrical stimulation of paralysed muscles

pedalled via ES-induced contractions of the paralysed lower-limb muscle groups [7]. Computer-controlled ES is used to induce contractions of the paralysed quadriceps, hamstring and gluteal muscle groups during an appropriate range of pedal angles to maintain smooth cycling. When pedalling at a 50 rpm target rate, a total of 300 muscle contractions per minute are induced. To control the cyclic ES pattern and current intensity, a microprocessor that receives pedal position and velocity feedback information from sensors is incorporated. As muscle fatigue progresses during an exercise period, ES current intensity automatically increases to a maximum of about 140 mA to recruit non-fatigued muscle fibres. When maximal current is reached and additional muscle fibre recruitment is no longer possible, the pedalling rate declines and ultimately falls below 35 rpm, at which time exercise is automatically terminated. Figure 7.1 illustrates operation of a commercially available ES-LCE by an individual with SCI.

ES Characteristics for Tissue Repair For tissue repair and enhancement of skin BF lower current levels are generally needed than for inducing muscle contractions. The total energy delivered to the affected tissue and electromagnetic changes in the wound environment depends on the current density, which is in turn determined by the electric current intensity and the electrode size, shape, and placement.

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Smaller electrodes concentrate the current, while large electrodes disperse the electric charge. When electrodes are placed further apart a deeper electric current will penetrate body tissues. Monophasic pulsed current (MPC) has been shown to be superior to constant direct current (DC). In some applications of MPC the cathode is placed initially in the wound area followed by a reversal to positive polarity (anode) after several days of treatment. In some applications the reversal is done periodically throughout the healing period. Three stimulation modalities are distinguishable: low-voltage direct current (LVDC), high-voltage pulsed direct current (HVPDC) and low-voltage alternating current (LVAC) (Table 7.1). There is considerable variability in the electrical parameters both among and within the three basic modalities. Applied currents are direct, alternating, continuous or pulsed (with different pulse frequencies), and waveforms are continuous, peaked (saw tooth), sinusoidal, square or triangular. In addition, there is at least a 1,000-fold difference in the range of magnitudes in the reported induced currents. Voltages vary; electrode placement and polarities are sometimes exchanged mid-treatment. Table 7.2 shows common stimulation characteristics for various electrical stimulation applications for tissue repair. Despite these striking differences, most of the diverse electrical adjuvant treatments are reported to be beneficial [8±10].

Table 7.1. Comparison of electric treatment modalities (from Scheffet et al. [8]) Electrical

Treatment modalities LVDC

HVPDC

LVAC

Voltage magnitude available

low (< 8 V)

high (6±200 V)

low (< 10 V)

Current type

DC

DC

AC

Average current intensity

20±999 lA

0.3±2.5 mA

15±25 mA

Waveform

Monophasic rectangular

Monophasic with sharp high peaks

Unbalanced biphasic/peaks

Pulse duration

100 ls

45±100 ls

250 ls

Pulse frequency (per second)

< 60

80±130

40±85

Treatment regimen (hours/day)

2±4

0.75±1

2

Electrode proximity placement

In wound

In wound

Edge of wound

Electrode reversal

Yes

Yes

No

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Table 7.2. Common stimulation characteristics for various electrical stimulation applications for tissue repair (From Cullum et al. [9]) Application

Type of stimulation

Phase duration current

Amplitude

Treatment duration

Oedema control

1. Pulsed or burst mode AC

>100 contraction

Rhythmic muscle

±a

2. High voltage, pulsed, negative polarity

2±50 threshold

90% of motor

30 min/4 h

1. Pulsed or burst mode AC

2

Sensory level

±a

2. Pulsed or burst

>100

>10% MVC

10 min

1. DC

NA

50% causes structural cell damage Strain >60% causes membrane bulging 72% strain: cells start to burst Dynamic straining: bulging at 40%, bursting at 54% Cells more sensitive to high frequency than low frequency

Bouten et al. [5]

Myoblasts and myotubes in agarose

1±24 h

Strain >20%: buckling of myotubes Strain >30±40%: buckling of myoblasts Increase in damage in cell after 1 h of straining

Wang et al. [16]

Myoblasts and myotubes in agarose

0.5±12 h

At 10% strain: increase in damage after 4 h compression At 20% strain: increase in damage after 0.5 h compression 60±70% of cell death due to apoptosis Myotubes more sensitive to straining than myoblasts

Breuls et al. [17]

Myoblasts and myotubes in collagen/matrigel mixture

1±8 h

At 30 and 50% strain: immediate cell damage At 30% strain: 50% damaged at 8 h At 50% strain: 80% damaged at 8 h

of compression. Clearly, the proportions of viable cells decreased with increasing strain magnitude. Furthermore, at constant strain magnitude, cell viability decreased with time of compression. It should be noted that these inverse relationships between magnitude and time of compression were related to cell deformation alone, rather than to impaired transport due to ischaemia, lymphatic occlusion, or reperfusion, which were not incorporated in the in-vitro models. The relative contribution of impaired oxygen transport to the observed cell damage, however, remains to be elucidated. So far, the effect of compression on the permeability of the tissue constructs for oxygen has not been quantified. Also, the effect of construct compression on the washout of waste products is not known. For example, in the work by Breuls et al., constructs were compressed under a 5-mm-diameter indenter and up to 50% strain, which could have limited transport

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Fig. 16.6. Combined percentages of viable cells in time from Bouten et al., (Bo [5]) Wang et al. (Wa [16]), and Breuls et al. (Br [17]). Percentages are normalised for the percentage cell death in unstrained controls

processes. If this effect is added to the possible squeezing out of oxygen upon load application, `ischaemia' could have influenced the observed cell damage. Nevertheless, the distribution of cell death under the indenter was homogeneous and not dependent on the distance of the cells to the edge of the indenter, as one might have expected to occur in oxygen diffusion-related damage evolution. In patient and animal studies the observed tissue damage is generally related to the pressure measured at the skin surface (or interface pressure). This pressure, however, is not representative of the local stresses and strains inside the tissue, which are relevant for tissue breakdown [21±24]. Local strains can differ considerably from externally applied loads and global tissue deformation at the body surface, as they are dependent on tissue geometry, tissue mechanical properties and local inhomogeneities, such as bony prominences. Likewise, the (damaging) strains applied in the current in-vitro models cannot be directly translated to clinically relevant interface pressures. For this purpose computational models that link stresses and strains at the cellular level to those at the tissue (surface) level are required [25]. Several authors have made attempts to estimate the strains arising near bony prominences in skeletal muscle tissue, using computational models (see Chap. 10). In a buttock model described by Oomens et al. [21], incorporating all tissue layers covering the ischial tuberosities, the overall strain throughout the muscle layer was determined to be about 15% during sitting (80-kg male). Considering the presented in-vitro results, this strain magnitude is damaging when applied for several hours. In another study,

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by Linder-Ganz and Gefen [26], the pelvic region of a lying subject (60-kg male) was modelled in more detail. Here tissue strains of up to 6% were found to occur in the longissimus muscle. These strains increased to 10% when bodyweight increased to 80 kg. Reger et al. [27] monitored deep tissue deformations in the pelvic region using MR imaging. Here, tissue deformation during compression was compared between paraplegic and normal female subjects. A clear difference in total tissue deformation between the two groups illustrates the importance of the physical condition of the patient. The tissue thicknesses from bone to skin at the trochanter and ischial tuberosities, were reduced by application of surface loads up to 60 mmHg. As a result, the compressive strains in the paraplegic group were in the range of 42±67%, whereas the normal group exhibited strains between 20 and 35%. The majority of the deformation was observed in the muscle tissue. Again considering the results summarised in Fig. 16.6, these strains can cause substantial damage with time. That is, taking into account that this figure is based on measurements in a murine cell line and not on human tissue. Obviously, apart from the duration and magnitude of tissue strains and possibly resulting transport impairments, other predisposing factors play a role in the onset of deep pressure ulcers. These may include factors such as immobility, age, malnutrition, medication, and dehydration, which affect the load-bearing capacities of the tissues, and factors like temperature and incontinence which influence the loads on the tissue. In-vitro models can contribute to the understanding of the fundamental processes underlying pressure ulcer development. The ability to control most predisposing factors independently of each other in these models can facilitate the quantification of the relative contribution of these factors to the aetiology of pressure ulcers.

Future Perspectives and Experiments The most important advantage of studying damage development in `in vitro' models of skeletal muscle is that the model can be very reproducible and easily controlled and manipulated. Cells can be genetically modified [18, 28], or stained to visualise the whole cell or a cellular protein of interest. For tissue engineering purposes also the ratio of tissue components (cells vs matrix) can be varied, and culture conditions can be monitored. The latter is especially relevant when studying the effects of external/risk factors on tissue damage. Hence, with respect to deep pressure ulcers, a tissue-engineered muscle model can be loaded with stress factors, such as anoxia or altered nutrient supply, via the surrounding medium and other culture conditions to simulate the influence of external risk factors on tissue viability. In order to study the influence of such predisposing factors on the development of deep pressure ulcers, an extended model system was designed in our lab. This system consists of three key components:

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1. A tissue-engineered skeletal muscle 2. A device that controls normal culture conditions, such as temperature and humidity, but that can also impose risk factors, such as compression and anoxia 3. A probe for real-time damage assessment, by monitoring expression of fluorescent markers and damage molecules that can be quantified in the culture media. With this model system, information can be obtained on the effect of several degrees of clinically relevant compressive strains (0, 20, 40%) with or without the effects of anoxia (0% O2) or normoxia (20% O2) on tissue viability. For both factors, compression and anoxia, damage development in time can be monitored and quantified, from viable (fluorescent) stainings and the release of cellular proteins in the culture medium. Muscle cell-specific proteins, such as myoglobin and creatine kinase, have the potential to serve as a future marker for pressure ulcer development in patients and hence are relevant candidate markers. In addition, specific fluorescent probes can provide information about the pathways of cell death (e.g. apoptosis vs necrosis). Extensions of this model can be employed to study the relative and combined contribution of compression, ischaemia, nutritional conditions, presence of reactive oxygen species, etc., on tissue breakdown with time and to discriminate between major and minor risk factors. This would result in stress±damage relationships as indicated in Fig. 16.7, which provides thresholds for irreversible tissue damage and hence guidelines for pressure ulcer prevention.

Fig. 16.7. Graph indicating the suggested response (from reversible damage to cell death) of muscle tissue to a predisposing factor for pressure ulcer development, such as strain, decreased oxygen tension or accumulation of metabolic waste products

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Summary Currently feasible in-vitro models of skeletal muscle cells and tissue assist in understanding the fundamental processes that underlie the development of pressure ulcers in muscle. In this chapter, several predisposing factors for deep pressure ulcer development are reviewed in combination with available in-vitro models. In particular, the influence of sustained cell deformation on the onset of tissue breakdown is described. The results of a series of deformation studies are summarised and demonstrate that cell deformation due to tissue compression plays a prominent role in the onset of tissue breakdown, where tissue breakdown is related to the time and magnitude of compression. The well-controllable in-vitro models have considerable potential for establishing damage thresholds in response to mechanical loading (tissue compression) with or without additional risk factors of pressure ulcer development.

References 1. Nola GT, Vistnes LM (1980) Differential response of skin and muscle in the experimental production of pressure sores. J Plast Reconstruct Surg 66:728± 733 2. Daniel RK, Priest DL, Wheatley DC (1981) Etiologic factors in pressure sores: an experimental model. Arch Phys Med Rehabil 62:492±498 3. Kosiak M (1959) Etiology and pathology of ischemic ulcers. Arch Phys Med Rehabil 40:62±69 4. Peirce SM, Skalak TC, Rodeheaver GT (2000) Ischemia-reperfusion injury in chronic pressure ulcer formation: a skin model in the rat. Wound Repair Regen 8:68±76 5. Bouten CV, Knight MM, Lee DA, Bader DL (2001) Compressive deformation and damage of muscle cell subpopulations in a model system. Ann Biomed Eng 29:153±163 6. Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P (1995) Stretch-induced programmed myocyte cell death. J Clin Invest 96:2247±2259 7. Vandenburgh HH, Hatfaludy S, Karlisch P, Shansky J (1991) Mechanically induced alterations in cultured skeletal muscle growth. J Biomech 24 Suppl 1:91±99 8. Emerson CP Jr (1993) Embryonic signals for skeletal myogenesis: arriving at the beginning. Curr Opin Cell Biol 5:1057±1064 9. Wigmore PM, Dunglison GF (1998) The generation of fiber diversity during myogenesis. Int J Devel Biol 42:117±125 10. Peeters EA, Bouten CV, Oomens CW, Baaijens FP (2003) Monitoring the biomechanical response of individual cells under compression: a new compression device. Med Biol Eng Comput 41:498±503 11. Peeters EA, Bouten CV, Oomens CW, Bader DL, Snoeckx L, Baaijens FP (2004) Anisotropic, three-dimensional deformation of single attached cells under compression. Ann Biomed Eng 32(10):1443±1452

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12. Peeters EA, Oomens CW, Bouten CV, Bader DL, Baaijens FP (2005) Loadbearing properties of single attached cells under compression. J Biomech (in press) 13. Peeters EA, Oomens CW, Bouten CV, Bader DL, Baaijens FP (2005) Viscoelastic properties of single attached C2C12 myoblasts. J Biomech Eng (IN PRess) 14. Bouten CV, Oomens CW, Baaijens FP, Bader DL (2003) The etiology of pressure ulcers: skin deep or muscle bound? Arch Phys Med Rehabil 84:616±619 15. Bouten CV, Breuls RG, Peeters EA, Oomens CW, Baaijens FP (2003) In vitro models to study compressive strain-induced muscle cell damage. Biorheology 40:383±388 16. Wang YN, Bouten CV, Lee DA, Bader DL (2004) Compression induced damage in a muscle cell model `in vitro'. Eng Med 219 part H:1±12 17. Breuls RG, Bouten CV, Oomens CW, Baaijens FP (2003) Compression induced cell damage in engineered skeletal muscle tissue: an in-vitro model to study pressure ulcer aetiology. Ann Biomed Eng 31:1357±1364 18. Vandenburgh HH (1998) Attenuation of skeletal muscle wasting with recombinant human growth hormone secreted from a tissue-engineered bioartificial muscle. Hum Gene Ther 9:2555±2564 19. Breuls RG, Mol A, Petterson R, Oomens CW, Baaijens FP, Bouten CV (2003) Monitoring local cell viability in engineered tissues: a fast, quantitative and non-destructive approach. Tissue Eng 9:269±281 20. Reswick J, Rogers J (1976) Experiences at Rancho Los Amigos Hospital with devices and techniques to prevent pressure sores. In: Kennedy RM, Cowden JM, Scales JJ (eds) Bed sore mechanics. Macmillan, London, pp 301±310 21. Oomens CW, Bressers OF, Bosboom EM, Bouten CV, Bader DL (2003) Can loaded interface characteristics influence strain distributions in muscle adjacent to bony prominences. Comput Methods Biomech Biomed Eng 6:171±180 22. Chow C, Odell E (1978) Deformations and stresses in soft body tissues of a sitting person. J Biomech Eng 100:79±86 23. Dabnichki P, Crocombe A, Hughes S (1994) Deformation and stress analysis of supported buttock contact. Proc IME part H: J Eng Med 208:9±17 24. Todd B, Thacker J (1994) Three-dimensional computer model of the human buttocks, in vivo. J. Rehab Res Dev 31(2):111±119 25. Breuls RG, Oomens CW, Bouten CV, Bader DL, Baaijens FP (2003) A theoretical analysis of damage evolution in skeletal muscle tissue with reference to pressure ulcer development. J Biomech Eng 125:902±909 26. Linder-Ganz E, Gefen A (2004) Mechanical compression-induced pressure sores in rat hindlimb: muscle stiffness, histology, and computational models. J Appl Physiol 96:2034±2049 27. Reger SI, McGovern TF, Chung KC (1990) Biomechanics of tissue distortion and stiffness by magnetic resonance imaging. In Bader DL (ed) Pressure sores: clinical practice and scientific approach. Macmillan, London, pp 177± 190 28. Vandenburgh H, Del Tatto M, Shansky J, Lemaire J, Chang A, Payumo F, Lee P, Goodyear A, Raven L (1996) Tissue-engineered skeletal muscle organoids for reversible gene therapy. Hum Gene Ther 7:2195±2200

Imaging Tissues for Pressure Ulcer Prevention

17

Martin Ferguson-Pell

Introduction Every day, clinicians determine tissue status by visual and physical assessment. These practices, although technologically simple, belie the complex range of physiological responses of the tissues that may be detected by clinical assessment. Observations made by clinicians are used to assess the integrity of tissues and their response to the mechanical, physical and chemical environment. Clinical observation, however, is limited in a number of important ways. Qualitative clinical assessment is difficult to record accurately, particularly when observations require recording of subtly different levels in tissue status or response. Different observers also often record qualitative observations differently. This often results in difficulties when working in teams or shifts, or when information is assessed over time. Imaging often requires qualitative interpretation of the information recorded, but the image at least captures information in a way that allows multiple assessors to view the same primary dataset. However, the nature of imaging systems in healthcare settings usually requires them to be operated by clinical and technical specialists working in a dedicated setting. They are usually used for diagnosis and screening in order to detect early evidence of pathologies, or to assist in the provision of interventions, such as surgery or radiotherapy. The potential for using imaging systems for the prevention and management of pressure ulcers is an altogether different proposition. With the prevalence of pressure ulcers in district general hospitals reported to be between 15 and 20% [1], use of specialist imaging facilities to assess wound status, or to identify particularly vulnerable patients, would create an overwhelming demand for scarce resources. Practical imaging systems to assist in pressure ulcer management must therefore be simple enough to use at the bedside. It may also be desirable for these systems to make measurements of parameters associated with the interaction of the patient with the bed or seating system, as it is here that problems with tissue integrity first occur. The cost of managing and preventing pressure ulcers certainly could justify the use of quantitative methods for tissue risk assessment and for monitoring the healing of ulcers. At present, however, confidence in the value of these technologies is modulated by their complexity, their cost and the lack of evidence of their efficacy.

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From the technology developers' perspective most of the technical requirements for instruments to provide reliable measurements of physiological or mechanical parameters can be fulfilled. However, a significant barrier to their development is the lack of sound physiological and aetiological understanding of pressure ulcer pathology, as highlighted in Chap. 1. Without a direct link to validated aetiological models, the design of effective clinical tools cannot be accomplished with confidence. For this reason many of the tools in use clinically have their origins as research instruments to measure specific physiological or mechanical parameters. They are most effectively used by clinicians, who use the information provided by these instruments to supplement their clinical skills and intuition. Much can, however, be learnt from work to date, from technologies developed for related application areas and from the use of instruments by researchers seeking to develop an improved understanding of the pressure ulcer problem. This chapter reviews many of these technologies and the insight they can provide into pressure ulcer aetiology.

Wound Assessment X-rays have in the past been used to assess the extent of necrotic undermining by injecting contrast media into the wound. The disadvantages of needing to use dedicated imaging services are obvious. A very simple way to record pressure ulcer dimensions is to use photography. With the advent of digital photography and the introduction of digital patient records it is much more practical for clinicians to record the progress of wound healing and to make simple measurements of changes in wound dimensions. Of course, a major limitation is that simple photography only yields information in two dimensions and therefore measurements of wound depth are not reliable from simple photographs. The Vision Engineering Research Group (VERG; Winnipeg, Canada) has produced a simple-to-use wound measurement system (VeV MD) using digital photography that provides reliable three-dimensional information. To achieve this, the VeV MD software uses target plates placed in the field of the image to determine the camera position and orientation in relation to the wound and corrects for the distortion caused by the curvature of the lens. With these correction techniques it is possible to record the area, length, width, perimeter, depth and volume, along with the hue of different regions of the wound. Easy-to-use software enables the clinician to track changes in all the parameters over time so that the progression of the wound healing process can be monitored. Figure 17.1 shows the target plate in position along with the margins of the wound that are detected automatically by the software. Of course, in cases where the tissues are undermined this system would fail to detect the full extent of tissue damage. Ultrasound imaging offers a more comprehensive means of wound assessment in these cases.

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Fig. 17.1. The VeV MD system in use, showing the target plate used to calculated wound dimensions and the margins of the wound detected by the software

Fig. 17.2. Use of B-mode ultrasonography for wound assessment (after Wendelken et al. [2])

The use of B-mode ultrasonography to provide a non-invasive record of the extent of wound undermining has been described in detail by Wendelken et al. [2]. This approach allows accurate monitoring of wound dimensions by filling the wound with a sterile wound-mapping gel and film dressing (Hudson Diagnostic Imaging). The wound is scanned by slowly moving the probe across the wound and a series of images captured digitally. (Fig. 17.2). Measurements of the wound can then be made using the digital

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Fig. 17.3. Ultrasound image of stage IV pressure ulcer being measured using digital callipers (after Wendelken et al. [2])

Fig. 17.4. Use of high-frequency ultrasonography to detect early pressure ulcer development (after Lyder [3])

callipers provided with the instrument's software package, as indicated in Fig. 17.3. Lyder [3] has used higher-frequency ultrasonography (Longport Inc., Swarthmore, PA, USA) to detect more subtle changes in tissues associated with a developing pressure ulcer. Lyder claims that experienced users of the system can differentiate phases of development, including pockets of oedema, inflammatory changes and frank breakdown (Fig. 17.4). Assessment of these images is a skilful process and open to differences in interpretation. Elastography is a non-invasive method for imaging tissues based on differences in the tissue stress±strain modulus associated with different tissue

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constituents and structures. Srinivasan et al. [4] have developed a technique using ultrasound that measures tissue strain and a nano-indenter which measures tissue modulus. By comparing the results from these two techniques on tissue phantoms they have demonstrated that there is an intrinsic relationship between tissue modulus and tissue strain. This offers a promising technique for future imaging of tissues where modulus changes are associated with pathology, for example the oedema associated with early pressure ulcer onset. A further development of elastographic technologies has been demonstrated by Sinkus et al. [5]. In this case, magnetic resonance imaging (MRI) is coupled with mechanical wave propagation. The tissue modulus can be inferred from the MRI data by taking a sequence of synchronised measurements at the maximum and minimum induced strains in the tissues during the application of the vibration. Further discussion of MRI applications is provided in Chaps. 12 and 18. Although these more advanced techniques do not at present offer practical everyday tools for patient assessment they are of real value in developing a more detailed understanding of pressure ulcer aetiology. With an improved understanding of the problem, more practical imaging techniques may well be evolved.

Pressure Measurement Numerous devices have been produced for single-point measurements, of which most successful for routine clinical measurements was the Talley-Scimedics Pressure Evaluator developed by Reswick and Rogers [6] for assessment of wheelchair cushion pressures. It comprised a thin elliptically shaped air bladder, approximately 100 ´ 80 mm, with a copper foil grid laminated to opposing surfaces of the inside of the bladder forming a switch. When the bladder was inflated the grid switches were `open', and when sufficient pressure was applied externally to the bladder it collapsed, causing the switch to `close'. This device had a number of technical limitations, not least its fragility and tendency to under-read when pressure was concentrated within its sensing area. However, it had the distinct advantages of low cost and ease of use, becoming widely adopted by clinicians needing a tool to measure interface pressures when assessing patients for wheelchair cushions and seating. A smaller sensor was later produced, based on similar principles, for making more localised single-point measurements; this device was thin enough to be considered suitable for measuring pressure beneath pressure garments and bandages. Its size and flexibility made it only practical to place directly on the skin prior to making interface measurements, whereas the Talley-Scimedics sensor could be positioned beneath the fully-clothed patient. The introduction of these interface pressure measurement systems into the clinical setting raised important issues about interpretation of the data and their validity. These concerns continue to be debated by clinicians, researchers and manufacturers of support surfaces who use pressure measurement to

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promote their products. Ferguson-Pell [7] proposed specifications for interface pressure sensors, pointing out that the sensors can introduce errors by locally perturbing the measurement region in which it is placed. The author proposed minimum specifications for the aspect ratio (ratio of thickness to diameter) of pressure sensors for different applications. Later, Ferguson-Pell and Cardi [8[ demonstrated the limitations of pressure-mapping systems in terms of their potential to hammock across the measurement region, in addition to measurement errors introduced by creep and hysteresis in the sensors. These studies and others have contributed to the widely established view that pressure-measurement systems are of clinical value when making comparisons between different support surfaces for an individual, where essentially qualitative information is required. The imaging of pressure between the body and a support surface is not a new technology. The earliest images were produced by Aronovitz et al. [9] and Reswick et al. [10] using a multicellular inflatable mat with 1886 independent reading of pressure made in rapid succession. A similar device was developed by Garber et al. [11], who produced the first commercial pressure-mapping system (TIPE System), which provided a spatial resolution of 144 sensors on a pad measuring 400 ´ 400 mm. This system was later modified by Jaros et al. [12] to enable the data to be displayed on a computer. Bader and Hawken [13] introduced the Oxford Pressure Monitor (OPM; Talley, UK), which used a novel pneumatic sensor to monitor 12 sensors placed at approximately 25 mm centres. In the early 1990s a number of pressure-mapping systems were introduced, filling the void left by the removal of the TIPE from the market due to man-

Table 17.1. Summary of four commercially produced pressure-mapping systems System

Novel Pliance

Tekscan

Xsensor

FSA

Manufacturer

Novel GmbH, Munich, Germany

Tekscan Inc., Boston, USA

Xsensor Technology Corp., Calgary, Canada

Vista Medical, Winnipeg, Canada

There are five models for wheelchairs Sensor type

Capacitive

Conductive ink

Capacitive

Conductive rubber

Single sensor area

600 mm2± 196 mm2

103 mm2

135 mm2

298 mm2

Sensor pitch

25 mm± 14 mm

10 mm

13 mm

25 mm

Number of sensors

256±1344

1558

1296

225

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ufacturing difficulties. Talley Medical Devices produced a 96-sensor array (Mk III, Talley Pressure Monitor). In Canada the QAPad was introduced, providing an electropneumatic system similar to the TIPE with 256 sensors placed on a 400 ´ 400 mm sensing area. Further developments were introduced using capacitive arrays of sensors by Novel (Munich, Germany) and by Xsensor (Calgary, Canada). Simultaneously, Vista Medical introduced the Force Sensing Array and Tekscan the SEAT System using semiconductor materials that decrease in resistance with increasing applied axial stress. Sample images are shown and the characteristics of these four systems are outlined in Table 17.1. As can been seen in Fig. 17.5, dramatic differences in pressure distribution are noted when a buttock phantom is loaded on a wide range of wheelchair cushions. The loading conditions are identical in each case, but the pressure distribution is significantly different due to the properties of the cushion. With the advent of the ability to measure interface pressure distributions came questions about how to interpret them (also discussed in Chap. 5). A number of proposals have been made for ªpeak acceptable pressuresº, many of them linked to physiological studies to determine capillary closure pressure. However Kosiak [14] and later Reswick and Rogers [6], emphasised the multi-factorial nature of pressure ulcer aetiology, not least that there is a nominal inverse relationship between applied pressure and the duration of its application to initiate a pressure ulcer. This inverse relationship is thought to be substantially modulated by other clinical risk factors and the loading history of the tissues. Bader [15], using tissue partial pres-

Fig. 17.5. Pressure maps generated by a gel-covered cushion loading indenter for a range of commercial cushions. The pressure map at top left is for a rigid surface for reference purposes

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sure of oxygen measurements, demonstrated how, under repetitive loading conditions, there were changes in tissue response with increasing number of loading cycles. Of course, pressure mapping images draw attention to differences in the way pressure is distributed spatially and thereby introducing third and fourth dimensions (pressure: amplitude, two spatial dimensions and time) to the measurements obtained from simpler instruments that are relevant to pressure ulcer aetiology. Drummond et al. [16] undertook an important study by measuring the distribution of pressure in wheelchairs beneath children with spina bifida. They defined an index by taking the ratio of the sum of the pressure readings in the sacral±ischial region to the sum of all readings on the cushion. Those children whose index was high, indicating that a greater proportion of the body weight was transferred to the cushions through their sacral±ischial tissues, were found to develop significantly more pressure ulcers. This study, coupled with that of Ferguson-Pell et al. [17], was the first to show in human subjects a link between pressure measurement parameters and actual pressure ulcer incidence. Subsequently Geyer et al. [18] undertook a comprehensive randomised prospective study which showed that peak pressure and average pressure were correlated with increased pressure ulcer incidence in a group of frail elderly people in a nursing home setting. Discussion of pressure measurement is not complete without addressing reasonable concerns for the biomechanical validity of these measurements. Interface pressure measurement strictly measures localised axial stresses that occur between two loading surfaces. These stresses are often referred to as contact stresses. Off-axis, or shear, stresses are known to occur and are thought to be of considerable clinical significance. Transducers to measure shear stresses have, however, presented significant technological challenges, although a number have been produced for research purposes. The level of shear stress is influenced by the direction of load transfer between the body and the support surface and the frictional properties of the interface. Interposing sensors will result in substantial changes in local shear unless the shear sensor matches the frictional properties of the interface materials. A satisfactory technological solution is still elusive. However, recognising that it is the physiological response of tissues to local mechanical stresses that determines their viability, many have suggested that measures of tissue deformation would yield measures more closely linked to the influence of a support surface on pressure ulcer risk. Cheung [19] and Sprigle et al. [20] employed instrumentation to measure the shape of the buttocks under loaded conditions and related the findings back to interface pressure readings. They found in a group of spinal injured participants that there were distinctive differences in loaded buttock shape linked to level of injury. They suggested that custom contoured seating could be used to accommodate these differences and thereby minimise tissue deformation during sitting. A buttock shape-sensing system was produced (Fig. 17.6) which enabled a record to be taken and input to a numerically controlled milling machine. Although the cushions did not match

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Fig. 17.6. Spring-loaded displacement sensors used to measure loaded buttock contour

the undeformed buttock shape, because the measurements were made with the tissues loaded on spring-loaded displacement sensors, this approach was thought to reduce tissue deformation compared with a planar cushion. There are concerns, however, that cushions formed to create an intimate fit might restrict opportunities to produce pressure redistribution through changes in posture. Nonetheless buttock shape-capturing technologies are being widely used for patients needing sophisticated postural management and where the risk of pressure ulcer development is relatively low.

Monitoring Tissue Response to Load Given the many limitations of pressure mapping, interest has been directed towards the use of physiological monitoring where the body's response to a support system is used to indicate its suitability. A number of discrete sensing systems have been used for this purpose, including transcutaneous measurements of the partial pressure of oxygen in the tissues [15], tissue reflectance spectroscopy (TRS) [21±23] and laser Doppler flowmetry (LDF) [24]. In all cases these instruments measure physiological changes in tissues associated with either the application of load generating ischaemia, or the reperfusion response (reactive hyperaemia) when the load is removed. Figure 17.7 illustrates TRS and LDF responses for a heel placed on an alternating pressure mattress during an inflation and deflation cycle. The cyclic variations in the LDF signal are associated with vasomotion.

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Fig. 17.7. Tissue response for a heel of a healthy subject placed on an alternating pressure mattress. The internal bladder pressure in one of the cells of an alternating pressure mattress is represented in black. The indices for skin blood content and oxygenation are indicated in blue and red, respectively, and the laser Doppler flux is represented in green

Laser Doppler Flowmetry Laser Doppler flowmetry imaging uses a stable monochromatic laser light source directed through a fibre optic to illuminate the tissue. Backscattered light is collected using a second fibre optic placed closed to the source (approximately 1.5 mm centres). The backscattered light will be slightly frequency shifted if the scattering medium, namely blood, is moving either towards (blue shift) or away from (red shift) the point of measurement. The net effect is for the bandwidth of the frequency spectrum of the backscattered light to be broadened by an amount proportional to the average velocity of the scattering medium. The tissue thickness sampled is typically 1 mm, the capillary diameters 10 lm and the velocity spectrum measurement 0.01±10 mm/s. Most LDF systems make single-point measurements providing an index of the blood flow rate. However, one scanning system (LDF Imager; Moor Instruments, Devon, UK) produces images of the blood flow in tissues by using a mirror to move the laser beam across the region of measurement in a raster pattern. This system can measure regions of tissue from 50 ´ 50 mm up to 500 ´ 500 mm, taking approximately 5 min to complete the scan. The maximum resolution of the system is 100 lm. A typical image of a healing burn is shown in Fig. 17.8.

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Fig. 17.8. Laser Doppler flowmetry image of healing burn with corresponding photograph (after Moor Instruments)

Transcutaneous Oxygen Measurement TcPO2 sensors employ a polarographic Clark electrode which comprises a platinum cathode held at 0.7±0.9 V relative to an anode usually made from silver. An oxygen-permeable membrane isolates the electrode from the skin. In order to measure the partial pressure of oxygen in the tissue the electrode is heated to 42±44 8C. This induces maximal vasodilation, so that the oxygen diffusing through the skin is equilibrated closely with arterial oxygen tension. Only discrete measurements are possible at present using TcPO2 sensors; however, a four-sensor system is available commercially for multi-point measurements (Perimed, Jårfålla, Sweden). These sensors have been used extensively by Bader [15]. Their repeatability for clinical applications is discussed by Coleman et al. [25].

Tissue Reflectance Spectroscopy Oxy- and deoxyhaemoglobin have distinctly different absorption spectra, particularly in the green and red regions of the spectrum as well as in the near infra-red (NIR) region of between 700 and 850 nm. A number of approaches have been adopted to use the absorption spectrum of light in the visible region to characterise the blood content and oxygenation of the superficial vasculature of the skin. Dawson et al. [26] employed the points on the absorption spectra for oxy- and deoxyhaemoglobin, known as the isobestic points (Fig. 17.9). The level of oxygenation does not influence the absorption of light at these wavelengths. These wavelengths are influenced by the concentration of blood in the sample volume and other factors, such as melanin. By taking ratios of neighbouring isobestic points (absorption = Lxxx at wavelength xxx), it is possible to derive indices for the blood concentration (H) in the sample volume, and its level of oxygenation (Ox). The indices proposed by Feather et al. [26] were:

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Fig. 17.9. The absorption spectrum of blood indicating the isobestic wavelengths



…L544 L527 Hˆ 16:5 Ox ˆ 100
‰…L573

…L573

L544 † 29

L558 †

…L558


100

…17:1†

L544 †Š=…14:5H†

…17:2†

As the blood concentration tends to zero, then Ox becomes indeterminate (one cannot measure haemoglobin oxygenation if there is no blood!) and in practice for low blood concentrations the signal-to-noise ratio becomes very low. Subsequently Ferguson-Pell and Hagisawa [22] proposed a slightly modified form of these equations for spectrometers with improved resolution. The isobestic wavelengths are shown in Fig. 17.9. Scattering is the dominant photon±tissue interaction in skin in the NIR wavelengths, whereas in the visible region light is strongly absorbed and therefore only penetrates the most superficial layers of the skin. Hebden and Delpy [27] and Hebden et al. [28] have demonstrated, using arrays of TRS optodes, that in the NIR it is possible to create images showing regions of differing blood oxygenation of the neonate brain. In Fig. 17.10 this technique is demonstrated for the forearm. It is also interesting to note that in the NIR an important terminal enzyme in the cellular respiratory chain (cytochrome oxidase, CtOx) produces in its oxidised state a broad peak around 830 nm [29]. This is not present for the enzyme in its reduced state. Thus it may prove possible to monitor and image the degree of oxygenation in tissues at a cellular level. However, due to the relatively strong absorption at these wavelengths this technique presents practical difficulties when decoupling the simultaneous contributions to the absorption spectrum of haemoglobin and CtOx. Ferguson-Pell and colleagues made discrete sensors to measure tissue reflectance spectra at interfaces between the body and support surfaces, and

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Fig. 17.10. NIR imaging of arm (left: optode array around circumference of arm; centre: X-ray image; right: NIR image) (after Elwell and Hebden [29])

Fig. 17.11. Schematic representation of a prototype array of sensors that use high-intensity LED illumination at centre wavelengths consistent with the isobestic points used by tissue reflectance spectroscopy to estimate levels of blood content and oxygenation

sample data are presented in Fig. 17.11. The dimensions of these sensors (10 mm diameter, 2.5 mm thickness) is approaching the aspect ratio requirement for pressure sensors at body±support interfaces [7]. They have also produced an array of sensors that offer the potential to image these parameters, using high-intensity light-emitting diodes with emission wavelengths close to the isobestic points used in the equations above (Fig. 17.9).

Summary Imaging techniques are available both to measure the interaction of the body with support surfaces and to assess tissue status. Ultrasound provides an effective method for assessing wound status, particularly in determining the extent of undermining of the wound. Photogrammetry techniques permit accurate measurement of wound dimensions using simple digital photography. Mechanical interaction with a support surface can be visualised using pressure mapping. There are, however, concerns regarding the accuracy of these devices and their influence on the supporting characteristics of some cushions and mattresses. The physiological response of tissues to ischaemia can be determined with a range of different techniques that provide information about blood

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flow, tissue oxygenation, and blood content and oxygenation. Imaging physiological parameters is challenging, especially if information is required while the tissue is under load. However, recent advances in electrooptics are reducing both the size and cost of sensors, suggesting a promising future for using the tissues as a direct indicator of their status, rather than drawing inferences from simple observation or pressure measurements alone.

References 1. Clark M, Bours G, de Flour T (2002) Summary report on the prevalence of pressure ulcers. Report European Pressure Ulcer Advisory Panel 2. Wendelken ME Markowitz L Patel M Alvarez OM (2003) Objective, non-invasive wound assessment using B-Mode ultrasonography. Wounds 15(11) 351±360 3. Lyder CHB (2004) Battling pressure ulcers: consistency means success. Nursing Homes Long Term Care Management 53(1):72±73 4. Srinivasan S, Krouskop T, Ophir J (2004) A quantitative comparison of modulus images obtained using nanoindentation with strain elastograms. Ultasound Med Biol 30(7):899±918 5. Sinkus R, Lorenzen J Schrader D, Lorenzen M, Dargatz M, Holz D (2000) High-resolution tensor MR elastography for breast tumour detection. Phys Med Biol 45:1649±1664 6. Reswick J, Rogers J (1976) Experience at Rancho Los Amigos Hospital with devices and techniques to prevent pressure sores. In: Kenedi RM, Cowden JM, Scales JT (eds) Bed sore biomechanics. MacMillan, London, pp 301±310 7. Ferguson-Pell MW (1980) Design criteria for the measurement of pressure at body/support interfaces. Eng Med 9:209±214 8. Ferguson-Pell MW, Cardi MD (1993) Prototype development and comparative evaluation of a wheelchair pressure mapping system. Assistive Technol 5:78±91 9. Aronovitz R, Geenway R, Lindan O, Reswick J, Scanlan J (1963) A pneumatic cell matrix to measure the distribution of contact pressure over the human body. Proc 16th Ann Conf Eng Med Biol, Baltimore 5:62±63 10. Reswick JB, Lindan O, Lippay A (1964) A device to measure pressure distribution between the human body and various supporting surfaces. Report No. EDC 4-6407, Medical Engineering Group, Case Institute of Technology and Highland View Hospital, Cleveland, Ohio 11. Garber SL, Krouskop TA, Carter RE (1978) A system for clinically evaluating wheelchair pressure-relief cushions. Am J Occup Ther 32:565±570 12. Jaros LA, Levine SP, Kett RL, Koester DJ (1988) The spiral pressure monitor. Proceedings of 3rd International Conference on Rehabilitation Technology, RESNA 308±309 13. Bader DL, Hawken MB (1986) Pressure distribution under the ischium of normal subjects. J Biomed Eng 8:353±357 14. Kosiak M (1961) Etiology of decubitus ulcers. Arch Phys Med Rehab 42:19±29 15. Bader DL (1990) The recovery characteristics of soft tissues following repeated loading. J Rehabil Res Dev 27:141±150 16. Drummond D, Breed AL, Narechania R (1985) Relationship of spine deformity and pelvic obliquity on sitting pressure distributions and decubitus ulceration. J Pediatr Orthop 5:396±402

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17. Ferguson-Pell MW, Wilkie IC, Reswick JB, Barbenel JC (1980) Pressure sore prevention for the wheelchair-bound spinal injury patient. Paraplegia 18:42±51 18. Geyer MJ, Brienza DM, Karg P, Trefler E, Kelsey S (2001) A randomized control trial to evaluate pressure-reducing seat cushions for elderly wheelchair users. Adv Skin Wound Care 14:120±129 19. Cheung KC (1987) Tissue contour and pressure distribution on wheelchair cushions. PhD Thesis, University of Virginia 20. Sprigle S, Cheung KC, Brubaker CE (1990) Factors affecting seat contour characteristics. J Rehab Res Dev 27:127±134 21. Hagisawa S, Ferguson-Pell MW, Cardi M, Miller SD (1994) Assessment of skin blood content and oxygenation in spinal cord injured subjects during reactive hyperemia. J Rehab Res Dev 31:1±14 22. Ferguson-Pell MW, Hagisawa S (1995) An empirical technique to compensate for melanin when monitoring skin micro circulation use reflectance spectrophotometry. Med Eng Phys 17:104±110 23. Sprigle S, Linden M, Riordan B (2003) Analysis of localized erythema using clinical indicators and spectroscopy. Ostomy Wound Management 49:42±52 24. Silver-Thorn MB (2002) Investigation of lower-limb tissue perfusion during loading. J. Rehab Res Dev 39:597±608 25. Coleman LS, Dowd GSE, Bentley G (1986) Reproducibility of TcPO2 measurements in normal volunteers. Clin Phys Physiol Meas 7:259±263 26. Dawson JB, Barker DJ, Ellis DJ, Grassam E, Cotterill JA, Fisher GV, Feather JW (1980) A theoretical and experimental study of light absorption and scattering by in vivo skin. Phys Med Biol 25:695±709 27. Hebden JC, Delpy DT (1997) Diagnostic imaging with light. Br J Radiol 70:S206±S214 28. Hebden JC Arridge SR Delpy DT (1997) Optical imaging in medicine. I. Experimental techniques. Phys Med Biol 42:825±840 29. Elwell J, Hebden JC (2004) http://www.medphys.ucl.ac.uk/research/borl/research/ nir_topics/imaging_exp. htm

Magnetic Resonance Imaging and Spectroscopy of Pressure Ulcers

18

Gustav Strijkers, Jeanine Prompers, Klaas Nicolay

Introduction In the previous chapters of this book, we have seen that pressure ulcers (decubitus ulcers) are extremely common in patients who are bed or chair bound, e.g. during hospitalization or because of spinal cord injuries. The ulcers can range from mild coloration of the skin to deep non-healing wounds, which extend into organs or bone. This complex pathology and aetiology of pressure ulcers makes a clinical evaluation by physical examination alone very difficult, if not impossible. Therefore, there is a great need for diagnostic methods to evaluate the depth and extent of pressure ulcers. With their ability to measure structural, functional and metabolic parameters in healthy and diseased tissue, magnetic resonance imaging (MRI) and spectroscopy (MRS) offer a variety of fast and non-invasive tools that can be used not only for diagnosis and suitable planning of treatment, but also for a better understanding of the mechanisms underlying the formation of pressure ulcers. In this chapter the current MR literature on pressure ulcers is discussed and new techniques that can be used in research and clinical diagnosis are proposed. The outline of the chapter is as follows. First the present role of MR techniques in pressure ulcer research is reviewed. Subsequently, a brief description of the basic principles of MR is given, followed by an explanation of a number of MR modalities and their (possible) applications in relation to the investigation of pressure ulcers. We conclude with a summary and perspective.

Present Role of MR Magnetic resonance imaging has proven an important non-invasive experimental tool in the detection and characterization of pathologies in the musculoskeletal system (see e.g. [1±7]). The technique offers excellent soft tissue contrast and high anatomical resolution. Therefore, it is rather surprising that there are only a few systematic MRI studies of pressure ulcers in humans and animal models, especially because MRI can provide the clues for a fast and accurate diagnosis, which might prove crucial for efficient medical or surgical treatment.

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Human clinical studies have been conducted mainly on debilitated patients with spinal cord injuries, who often develop chronic pressure ulcers (see other chapters of this volume). In a study by Hencey et al. [8], 37 male spinal cord injury patients who had current or recent sacral, ischial or peritrochanteric pressure ulcers were examined with MRI. It was concluded that MRI could play an important role in the clinical evaluation of decubitus ulcers. The technique was able to detect the extent of soft tissue changes, adjacent fluid collection and the involvement of bone. In contrast, Rubayi et al. [9] reported a case study of six spinal cord injury patients with iliopsoas abscess evaluated by MRI, computed tomography (CT), conventional radiography, and radionuclide scanning. Iliopsoas abscesses were best diagnosed and treated using CT. From this study it was concluded that CT was superior to MRI and other radiographic methods. More recently Huang et al. [10] evaluated the clinical accuracy of MRI was in the diagnosis of osteomyelitis in the pelvis/hips of 44 paralysed patients and the utility of MR mapping of the disease extent as a guide to the extent of surgical resection. It was found that MRI is able to diagnose the associated findings in spinal cord-injured patients and can also guide the surgeons as to the anatomic extent, allowing accurate and limited treatment. Ruan et al. [11] also evaluated the use of MRI in making clinical decisions when assessing non-healing pressure ulcers and non-healing myocutaneous flaps for the presence of abscesses, osteomyelitis, sinus tracts and fluid collections. This was done in 12 patients as part of their pre- and postoperative diagnostic evaluation. A number of case studies illustrated the complicated treatment and evaluation. It was concluded that MRI could be used to identify and evaluate the pressure ulcers in the preoperative period. To our knowledge, there are only a few histological animal model studies on pressure ulcers [12±15], and only one that combines histology and MRI [16]. In the latter work decubitus ulcers were induced in the tibialis anterior muscle and overlying skin in the right hind limb of the rat by compression from an indenter over the tibia. MR images were obtained in vivo 24 h after load application, and subsequently tissues were processed for ex vivo histological examination. The amount and extent of the damage determined with MRI and from histology were in good agreement. It was concluded that MRI, as it is non-destructive, is a promising alternative for histology in research on pressure ulcer aetiology and, especially, in followup studies to evaluate the development of muscle damage over time and in clinical studies. The studies above, although limited in number, have clearly shown that MRI can be a useful tool for the clinical assessment and in the research of the aetiology of pressure ulcers. However, apart from the use of MRI, to provide basic contrast and mainly anatomical information, there are a number of MRI modalities available nowadays that have found no application in pressure ulcer research yet. Tagging MRI, diffusion-weighted MRI and perfusion MRI offer the possibility to measure local muscle fibre de-

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formation, orientation and tissue perfusion, respectively. Magnetic resonance elastography measures the viscoelastic properties of muscle in relation to health and disease. Finally, with MRS the concentration of low-molecular-weight metabolites can be determined, which provides information on the biochemical status of tissues. The principles of these additional and alternative MR modalities and their potential value in pressure ulcer research will be discussed in the next sections of this chapter.

MR Techniques Basic Principles and Practical Considerations Nuclear magnetic resonance (abbreviated to MR in the biomedical literature) is a physical technique that is based on the fact that most atomic nuclei have a magnetic moment. When a large number of such nuclei are placed in a strong magnetic field, this leads to the generation of a net spin magnetization that can be detected with a radio-frequency receiver coil, after excitation by a short radio-frequency pulse. Many nuclei can be detected by MR, of which 1 H, 13C, and 31P are most relevant in biological tissues. MR as applied in vivo has two basic modalities, MRI and MRS. MRI of biological systems is usually based on the measurement of the distribution of the hydrogen nuclei of water. The use of water as a probe molecule has many advantages: (1) the hydrogen nucleus has the highest sensitivity among biologically relevant nuclei; (2) water is present in high concentrations in most tissues; (3) the magnetic properties of water are sensitive to the local microstructure and composition of biological tissues as well as to environmental factors such as temperature and pH; (4) water displacement inherent to processes like diffusion, perfusion, flow, and movement can be quantified by specific MRI measurement sequences; and (5) the magnetic properties of the hydrogen nuclei in water can be modulated by interactions with paramagnetic entities, which are either endogenous to the tissue (e.g. deoxyhaemoglobin in the red cells of the blood) or can be injected as an exogenous contrast agent (examples include chelates of rare earth metal ions, or targeted nanoparticles containing paramagnetic centres). The above factors explain the rich spectrum of image contrast parameters for which MRI is so well known. As an imaging technology, MR has advanced considerably in the past 10 years, but it continues to evolve and new capabilities and applications will likely be developed (for introductory reading see [17±21]). A MR system consists basically of the following components. A large magnet provides the static magnetic field. Radio-frequency coils transmit and receive the radio signals. Magnetic field gradient coils provide the spatial localization of the signal, and a computer is used to reconstruct the radio signal into the final image or spectrum. The MR examination of humans is usually carried out within the radiology department of a hospital. The patient is positioned on a narrow bed within the magnet and the MR

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technologist or radiologist performs the examination. An entire examination may take from 20 min to 1.5 h, depending on the type and amount of information required. The design of the MR system restricts the subjects to a horizontal lying position inside the bore of the magnet. This means that tissue deformation, relevant to pressure ulcer research, can be examined only in a lying position, not under realistic conditions in a sitting position, such as when a patient is confined to a wheelchair. MR has no known negative effects on living tissue, but some potential hazards, related to metal objects entering the scan room, should be considered. Because of possible interference with the high magnetic and RF fields present, patients who have a heart pacemaker, surgical staples, aneurysm clips, or any other implanted metal device are not allowed to undergo a MR scan. The MR examinations of animals are similar to those of humans, except that the animals are usually sedated to avoid movement during the scans. This also allows for longer scanning times, up to several hours. MR examinations on small laboratory animals are usually performed with specialized high-field animal scanners.

Basic Contrast The proton density, and the T1 and T2 relaxation times provide the basic contrast in MR images. The proton density is the distribution of water in tissue, which gives the main anatomical contrast in the images. The brightness of pixels in the MR images also depends, however, on the chemical and physical environment of the protons, which can be described by T1 and T2. The spin-lattice or longitudinal relaxation time T1 describes the exponential increase of the spin magnetization towards equilibrium when placed in a strong magnetic field or when disturbed by a radio-frequency pulse. The spin-spin or transverse relaxation time T2 describes the exponential decrease of the spin magnetization in the transverse plane (perpendicular to the static magnetic field). This transverse magnetization, which is created by tipping the spin magnetization from longitudinal equilibrium by a radio-frequency pulse, creates the measured signal in MRI. The intensity of the MR signal is given in first approximation by I / Ne

TE=T2

…1

e

TR=T1

†

…1†

where N, T1, and T2 are the proton density, the spin-lattice relaxation time and the spin-spin relaxation time, respectively. TR is the radio-frequency pulse repetition time and TE is the echo time, or signal delay time. Contrast is obtained because different tissues have different proton densities and relaxation times [22±25]. Equation 1 shows that when TR is long and TE is short compared to T1 and T2, respectively, the contrast is mainly determined by the proton density, yielding a so-called proton density-weighted image. When TR is of the order of the spin-lattice relaxation time, contrast is ob-

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tained on the basis of differences in T1, in which case the image is called a T1weighted image. When TE is of the order of the spin-spin relaxation time, contrast is obtained on the basis of differences in T2, resulting in a so-called T2-weighted image. Note that Eq. 1 holds only for a spin-echo imaging pulse sequence. For other imaging pulse sequences the intensity depends in a more complicated manner on N, T1, and T2 [20]. The spin-lattice relaxation time T1 depends on the motion of water molecules in tissue and the interactions with surrounding macromolecules. The spin-spin relaxation time T2 is in addition strongly affected by the slowly varying magnetic fields at the molecular level. A detailed discussion of the physical and chemical origin of the relaxation processes in living tissue is beyond the scope of this chapter. It is more useful to consider the relaxation times typically observed in musculoskeletal tissues and the effects of pressure ulcer pathology on these relaxation times. Table 18.1 shows typical relaxation times at 1.5 T for some relevant tissues. The relevant pathologic conditions of pressure ulcers that affect muscle proton density and relaxation times are inflammation, haemorrhage, mass lesions, fibrosis, and fatty infiltration [1, 7]. Inflammation, oedema and haemorrhage usually lead to an increased proton density, caused by increased intracellular and extracellular free water. The T1 and T2 are increased because free water has longer relaxation times. Most mass lesions, such as solid neoplasms, abscesses and tumours, also are characterized by relaxation times that are prolonged relative to the surrounding tissues. Because both inflammatory processes and mass lesions lead to increased relaxation times, differentiation on the basis of relaxation times only is difficult. However, usually a clear distinction between the two can be made on the basis of morphology. Fibrous tissue formed by fibrosis does not provide much MR signal, due to low water content, and may be difficult to detect until a substantial amount of tissue has formed. Fat is characterized by a short T1, and T1-weighted MRI can therefore easily detect fatty infiltration. Because of the well-documented effects of muscle pathology on the proton density and the relaxation times, contrast in proton density-weighted, T1-weighted and T2-weighted MRI provides a useful tool for the detection and diagnosis of pressure ulcers [8±11, 16]. This is illustrated in Fig. 18.1, showing transverse T2-weighted MR images of the hind limbs of three rats Table 18.1. Typical relaxation times for relevant human tissues at 1.5 T [22±25] Tissue

T1 (ms)

T2 (ms)

Muscle

1077

47

Adipose tissue

260

84

Nerve

740

77

Bone marrow

250

25

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Fig. 18.1 a±c. Transverse T2-weighted MR images of the hind limbs of three rats, 24 h after induction of a pressure sore in the tibialis anterior muscle (TA). Bright areas correspond to regions of muscle damage (V ventral, D dorsal). Reproduced with permission from Bosboom et al. [16]

24 h after induction of a pressure ulcer in the tibialis anterior muscle by compression [16]. Patchy regions with high signal intensity are observed in the muscle, probably caused by oedema due to inflammation. The amount of muscle damage assessed in vivo with MRI correlated well with the area of damage obtained from ex vivo histology.

Dynamic Deformation In a number of recent studies it has been hypothesized that prolonged deformation of cells plays a major role in the onset of tissue damage [16, 26± 31]. This hypothesis was tested on cultured cells [28, 31] and in a rat model in which the tibialis anterior muscle and overlying skin were compressed between an indenter and the tibia [16, 29, 30]. For the rat model, the amount and location of the pressure ulcers that developed were determined with histology and MRI (see Fig. 18.1), and the results were compared to finite-element calculations of shear strain distributions in the muscle during loading. Unfortunately, most calculations resulted in shear strain distri-

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butions not corresponding to the location and amount of muscle damage observed. The discrepancy was attributed mainly to insufficient knowledge about the exact deformations of the muscle induced by the indenter. We propose an approach using MRI to locate the exact position of the indenter and the resulting amount of global deformation of the muscle. Figure 18.2 shows an ex vivo coronal MR image of the lower hind limb of a rat. In the image an indenter is visible, pressed into the tibialis anterior muscle. The indenter is visible because it is fabricated of a hollow Perspex tube, filled with regular water. The Perspex tube itself is not visible, but since the dimensions of the tube are known, the exact three-dimensional position of the end of the tube can easily be extrapolated from the position of the water in the tube. In this way the indenter can be pressed into the muscle in a precise and reproducible manner. The ex vivo MR image in Fig. 18.2 was recorded for demonstration purposes. The technique works in vivo as well. With MR tagging it is possible to measure the three-dimensional tissue deformation also locally [32]. This technique uses a set of preparation radiofrequency pulses to produce a periodic modulation of the longitudinal magnetization prior to imaging. The resulting images show a characteristic striped or checkerboard pattern. Motion (deformation) between the time of preparation and imaging will show up as a displacement of the pattern. This technique is widely used to measure heart wall motion [33]. MR tagging can also be used to measure contraction and deformation of skeletal muscle. This is demonstrated in Fig. 18.3, which displays in vivo MR tagging images of a mouse hind leg at rest and during contraction by stimulation of the scia-

Fig. 18.2. Coronal ex vivo MR image of a rat hind limb with a water-filled indenter pressed into the tibialis anterior muscle. Courtesy of A. Stekelenburg and G. J. Strijkers, Eindhoven

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Fig. 18.3. Coronal in vivo MR tagging images of a mouse hind limb a at rest and b during contraction by stimulation of the sciatic nerve. Courtesy of A. M. Heemskerk, Eindhoven and M. R. Drost, Maastricht

tic nerve. By combining a set of slices at different positions and orientations, the three-dimensional local movements, deformation and stresses in the muscle can be determined. This technique can also be used in combination with the indenter shown in Fig. 18.2 to obtain accurate information about the exact deformation of the muscle under external pressure conditions.

Diffusion Weighting and Diffusion Tensor Imaging The random motion (diffusion) of water molecules in living tissue can be measured with MR by using diffusion-weighted sequences, such as developed by Stejskal and Tanner [34]. Diffusion weighting can be achieved by introducing a set of pulsed magnetic field gradients, which subsequently dephase and rephase the proton spin magnetization. In tissue with diffusion, signal loss is observed, because moving spins are not completely rephased by the gradients. Diffusion of water in biological tissue is composed of the random motion of water in the intra- and extracellular compartments as well as exchange processes. Diffusion-weighted imaging (DWI) can yield important information about the condition of healthy and pathological tissues [35]. DWI has been applied most extensively in the brain, in which it is highly sensitive to the detection of brain ischaemia in an early stage of development [36]. Necrotic tumour tissue can be differentiated from viable tissue by an increased diffusionrelated signal loss [37±39]. Oedema, inflammation, and haemorrhage in soft tissue lead to increased free water content and therefore to strong diffusion attenuation of the signal in DWI [40]. It is expected that DWI might therefore prove useful in the detection and diagnosis of skeletal muscle pressure ulcers. A high degree of orientation in tissue leads to anisotropy of the diffusion. This can be observed, for example, in white matter tracts in the brain [41±

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Fig. 18.4 a, b. Two slices of an ex-vivo diffusion tensor image of a mouse hind limb. The lines indicate the in-plane direction of preferential water diffusion, corresponding to the local muscle fibre orientation. The DTI data are plotted on top of a regular T2-weighted MR image. Courtesy of A. M. Heemskerk and G. J. Strijkers, Eindhoven

44], but also in muscle [45±50]. Water diffusion along fibres is relatively fast, while diffusion perpendicular to the fibres is restricted. By measuring the directional dependence of the water diffusion and using the diffusion tensor concept for data analysis, the orientation of the fibres can be determined in three dimensions. This technique is called diffusion tensor imaging (DTI). Figure 18.4 shows two slices of a diffusion tensor image of a mouse hind leg. The lines indicate the in-plane direction of easy water diffusion, corresponding to the local muscle fibre orientation. The DTI data are plotted on top of a regular T2-weighted MR image. Muscle damage might lead to a localized decrease in the diffusion anisotropy. The muscle fibre orientation can provide input for mathematical finite-element models of skeletal muscle mechanics, relevant to pressure ulcer formation [16, 29, 30]. DTI can be combined with MR tagging to determine fibre orientation during contraction or deformation.

Perfusion The aetiology of pressure ulcers is very complicated. One of the competing hypotheses suggests that local ischaemia of the tissue, caused by occlusion of the capillaries under pressure and subsequent reperfusion damage by oxygen free radicals, is an important trigger for the development of pres-

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sure ulcers (refs. [12, 13, 15, 51, 52] and Chap. 13 of this volume). Measurement of local perfusion and reperfusion of skeletal muscle could provide important clues concerning the development of pressure ulcers. A number of techniques are available for measuring perfusion in skeletal muscle, such as strain-gauge plethysmography, the use of microspheres, radioactive tracer methods, thermodilution measurements and laser Doppler velocimetry [53±56]. None of these, however, is capable of providing the high temporal and spatial resolution desired when measuring in vivo muscle. MR, on the other hand, does offer a range of techniques to measure perfusion. Presently, most MR perfusion studies have been applied to the brain [57, 58], in which perfusion is higher and easier to measure than in skeletal muscle. Nevertheless, recent studies have demonstrated convincingly that perfusion measurements with high temporal and spatial resolution are possible in skeletal muscle too [59, 60]. Measurements of muscle perfusion with MR can be classified in two major techniques: the endogenous and the exogenous tracer methods. The first method uses endogenous water in blood as a contrast agent and is often called the arterial spin labelling (ASL) technique. ASL uses radio-frequency pulses to label the spin magnetization of arterial blood by inverting or saturating its magnetization. The labelled water molecules are delivered to the imaging slice by flow, followed by exchange with tissue protons. A control experiment is performed without labelling. The difference signal of control and labelled images, in which static tissue signals are identical, originates from blood that has perfused into the tissue only. Several ASL techniques have been designed, differing in how and at which position the blood is labelled [57, 58]. The drawback of ASL lies in its relatively low sensitivity and in the fact that quantification of the absolute perfusion is difficult and needs extensive mathematical modelling. The ASL technique is demonstrated in Fig. 18.5, showing perfusion images of the lower legs of four healthy volunteers. The images were recorded after the subjects had finished an exercise protocol in a plantar-flexion ergometer with weights of 10 lb (4.5 kg) and 20 lb (9.1 kg). Variations in perfusion rates with weight are clearly visible. Perfusion increases are associated with distinct muscle groups. Clear variations between different subjects can also be observed. The perfusion measurements were consistent with those obtained by traditional techniques. The results of this study show that perfusion measurements of skeletal muscle with the ASL technique are feasible. The second perfusion MRI technique uses an exogenous paramagnetic contrast agent, such as gadolinium-DTPA. Following an intravenous injection of the contrast agent, the delivery of the agent to the tissue can be made visible with T1-weighted fast MRI sequences. Recently this technique was successfully demonstrated in a rat model of hind-limb ischaemia [60]. After femoral artery ligation of one of the hind limbs, the remaining perfusion reserve was quantified using the Gd-DTPA uptake rate, obtained using a T1-weighted fast imaging technique. Perfusion was also measured during hyperaemia, caused by stimulation of the sciatic nerves of both hind limbs. Figure 18.6 a shows the perfusion index for a cross section of the non-li-

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Fig. 18.5. a Anatomical axial MR images of the lower leg of four human subjects. b Perfusion images for both the 10-lb and the 20-lb exercise protocol. Courtesy of L.R. Frank et al. [59]: ªDynamic imaging of perfusion in human skeletal muscle during exercise with arterial spin labeling,º Magn Reson Med 42, Copyright ° 1999. Reprinted by permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc

gated and ligated hind limbs, at rest and after stimulation. The MR signal enhancement can be assumed to be proportional to the Gd-DTPA concentration, and the perfusion index was defined as the maximum Gd-DTPA uptake. The reduced perfusion index due to the ligation during hyperaemia is obvious. Very good agreement was observed between the MR perfusion data and microsphere blood flow measurements. In Fig. 18.6 b the time course of the perfusion index during hyperaemia is shown from 1 h to 42 days after ligation, demonstrating that this technique can be applied reproducibly during a long period of time. As shown, both endogenous and exogenous tracer methods have been successfully used to measure local perfusion in skeletal muscle. This opens the possibility of non-invasive measurement of perfusion changes in mus-

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Fig. 18.6. a Examples of perfusion index maps from the hind limb muscles of a control rat and a rat with femoral artery ligation of one of the hind limbs, in resting condition and during stimulationinduced hyperaemia. The perfusion index was obtained with MR perfusion measurement using the contrast agent Gd-DTPA. b Time course of the perfusion index during hyperaemia after ligation. The bars indicate different muscle groups. From left to right: tibialis cranialis, tibialis caudalis plus flexor digitorum longus, gastrocnemius, and total muscle groups in the cross section. Courtesy of Y. Luo et al. [60]: ªEvaluation of tissue perfusion in a rat model of hind-limb muscle ischaemia using dynamic contrast-enhanced magnetic resonance imaging,º J Magn Reson Imaging 16, Copyright ° 2002. Reprinted by permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc

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cle during applied pressure and following reperfusion in relation to pressure ulcer formation. MR provides the possibility to measure acute changes in muscle perfusion on a short timescale. In addition, subtle changes in perfusion rates over extensive periods of time can be followed reproducibly. This might provide important new clues needed for unravelling the aetiology of pressure ulcers.

Magnetic Resonance Elastography It is well known that a variety of disease processes lead to a change in the visco-elastic properties of tissue. A relatively new diagnostic method for detecting changes in the mechanical properties of tissue is magnetic resonance elastography (MRE) [61±64]. MRE can be applied to a variety of tissues. So far the technique mainly has been successful in the detection of tumours [65± 68] (e.g. in the breast or brain), which are observable as stiff solid masses in the MRE images. Little is known about the elastic properties of muscle in vivo, and present MRE studies of muscle are therefore mainly focused on determining the mechanical properties of healthy muscle [69±72]. We anticipate that MRE can also be used to detect changes in muscle elasticity caused by decubitus ulcers in an early stage of development. In brief, MRE works as follows: With MRE it is possible to directly visualize propagating acoustic strain waves in tissue. These waves are introduced into the tissue by excitation with a mechanical transducer. A velocity-sensitive phase-contrast MRI method is used to measure the small displacements when the waves propagate in the tissue. From these displacements, the velocity, wavelength and attenuation of the shear waves can be determined. Stiff material is characterized by a long wavelength and high wave velocity, elastic material by a short wavelength and low velocity. Figure 18.7 shows an example of MRE of the biceps brachii muscle of a healthy volunteer [69]. In this investigation MRE was applied to quantify the changes in stiffness of skeletal muscle under load. In Fig. 18.7 a a schematic diagram of the experimental set-up is shown. The transducer, which excites the biceps tendon periodically, is placed on the skin. The volunteer holds a load of 4 kg. Figure 18.7 b shows the conventional axial MR image of the arm, with the slice position of the coronal MRE wave image indicated by the rectangle. Figure 18.7 c shows the MRE shear wave pattern at a single phase propagating in the coronal slice of the biceps. Combining wave images at different phases enables visualization of the propagating waves through the tissue. For the characterization, modelling and diagnosis of pressure ulcers in skeletal muscle, MRE might be a very useful tool. Although no experimental evidence is available yet, we anticipate that oedematous ulcers will be visible as regions of changed elasticity [65]. MRE can provide the material parameters, needed for finite-element modelling of muscle deformation in relation to the formation of pressure ulcers (ref. [16] and Chap. 12 of this book).

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Fig. 18.7. a Schematic diagram of the set-up for the MRE measurements of the biceps brachii muscle under loading conditions. b Normal axial MR image of the arm. c MRE wave image at a single phase in the coronal slice indicated by the rectangle in b. Courtesy of M. A. Dresner et al. [69]: ªMagnetic resonance elastography of skeletal muscle,º J Magn Reson Imaging 13, Copyright ° 2001. Reprinted by permission of Wiley-Liss Inc., a subsidiary of John Wiley & Sons, Inc

Magnetic Resonance Spectroscopy In vivo 1H and 31P MRS might yield information of potential value in pressure ulcer research. 1H spectroscopy provides a window on energy and fat metabolism, while 31P MRS yields more specific biochemical information on tissue bioenergetics (for introductory reading see e.g. refs. [18, 21, 75]). Figure 18.8 shows examples of 1H and 31P NMR spectra from human skeletal muscle, using a magnetic field of 1.5 T. The most sensitive nucleus for MRS is 1H. Figure 8 a shows a localized 1 H NMR spectrum of human skeletal muscle. During acquisition the high

a

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331

b

Fig. 18.8. a Localized 1H NMR spectrum of human skeletal muscle. b 31P NMR spectrum of human skeletal muscle. Courtesy of J. J. Prompers, Eindhoven

signal from free water is suppressed, to obtain a spectrum with the peaks of several metabolites that contain protons. From left to right the peaks correspond to methyl and methylene protons of creatine and phosphocreatine (total creatine = tCr), to protons in trimethylammonium groups (TMA), and to methyl and methylene protons of extra- and intramyocellular lipids (EMCL and IMCL). Creatine and phosphocreatine serve as a major energy buffer in muscle, and fatty acids are the main fuel for ATP synthesis. Lactate, an important marker for tissue ischaemia and hypoxia [75± 78], cannot be observed in this spectrum because it is masked by the large lipid signals and occurs only in low levels in resting muscle. Two-dimensional NMR or spectral editing techniques are necessary to observe lactate in human skeletal muscle [78±81]. Figure 18.8 b shows a 31P spectrum of human skeletal muscle. From left to right the peaks correspond to inorganic phosphate (Pi), phosphocreatine (PCr), and the three phosphate groups (a, b, c) of ATP. The 31P spectrum reflects the metabolic state of the tissue. Biologically relevant parameters, such as intracellular pH, free magnesium concentrations, and ADP concentrations, can be deduced. MRS is much less sensitive than MRI because it measures metabolites that are present in millimolar concentrations, while tissue water that is utilized for MRI is present in bulk amounts. Consequently, MRS is usually restricted to measuring signal from a relatively large amount of tissue. For example, a rough estimate shows that a minimum volume of 30 cm3 is needed to measure the 31P ATP signal of skeletal muscle at 1.5 T with sufficiently high signal-to-noise ratio [81]. Volume selection can be achieved by applying single-voxel localization techniques or by using surface coils, which record the signals from a restricted area only. Multi-voxel localization and spectroscopic imaging techniques can be used to obtain spatially resolved metabolic information [21].

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Summary and Future Perspective As we have illustrated, there is a broad range of structural, functional, as well as metabolic parameters that can be measured non-invasively by MRI and MRS under in vivo conditions in humans and laboratory animals. This makes MR ideally suited for the detection and characterization of pressure ulcers. Most MRI and MRS techniques can be combined in a single experiment, which makes the information density of MR very high. T1, T2 and diffusion weighting provide the basic contrast, capable of detecting pressure ulcer pathology, e.g. oedema, inflammation and haemorrhage. Perfusion MR and MRS capture the nutrient flow and metabolic state of the tissue. Combinations of MR tagging, diffusion tensor imaging and MRE can provide information on geometry, fibre orientation, deformation behaviour and material parameters, indispensable for the mathematical modelling of the behaviour of muscle under pressure. To conclude, MR is expected to gain importance and establish itself as an essential tool both in the clinical assessment of pressure ulcers and in research on pressure ulcer aetiology.

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49. Sinha U, L Yao L (2002) In vivo diffusion tensor imaging of human calf muscle. J Magn Reson Imaging 15:87±95 50. Bonny JM, Renou JP (2002) Water diffusion features as indicators of muscle structure ex vivo. Magn Reson Imaging 20:395±400 51. Kosiak M (1966) An effective method of preventing decubital ulcers. Arch Phys Med Rehabil 47:724±729 52. Dinsdale SM (1974) Decubitus ulcers: role of pressure and friction in causation. Arch Phys Med Rehabil 55:147±152 53. Guy RH, Tur E, Maibach HI (1985) Optical techniques for monitoring cutaneous microcirculation: recent applications. Int J Dermatol 24:88±94 54. Raynaud JS, Duteil S, Vaughan JT, Hennel F, Wary C, Leroy-Willig A, Carlier PG (2001) Determination of skeletal muscle perfusion using arterial spin labeling NMRI: validation by comparison with venous occlusion plethysmography. Magn Reson Med 46:305±311 55. P. Nuutila, Kalliokoski K (2000) Use of positron emission tomography in the assessment of skeletal muscle and tendon metabolism and perfusion. Scand J Med Sci Sports 10:346±350 56. Saltin B, Radegran G, Koskolou MD, Roach RC (1998) Skeletal muscle blood flow in humans and its regulation during exercise. Acta Physiol Scand 162:421±436 57. Barbier EL, Lamalle L, Decorps M (2001) Methodology of brain perfusion imaging. J Magn Reson Imaging 13:496±520 58. Calamante F, Thomas DL, Pell GS, Wiersma J, Turner R (1999) Measuring cerebral blood flow using magnetic resonance imaging techniques. J Cereb Blood Flow Metab 19:701±735 59. Frank LR, Wong EC, Haseler LJ, Buxton RB (1999) Dynamic imaging of perfusion in human skeletal muscle during exercise with arterial spin labeling. Magn Reson Med 42:258±267 60. Luo Y, Mohning KM, Hradil VP, Wessale JL, Segreti JA, Nuss ME, Wegner CD, Burke SE, Cox BF (2002) Evaluation of tissue perfusion in a rat model of hind-limb muscle ischemia using dynamic contrast-enhanced magnetic resonance imaging. J Magn Reson Imaging 16:277±283 61. Muthupillai R, Lomas DJ, Rossman PJ, Greenleaf JF, Manduca A, Ehman RL (1995) Magnetic resonance elastography by direct visualization of propagating acoustic strain waves. Science 269:1854±1857 62. Muthupillai R, Rossman PJ, Lomas DJ, Greenleaf JF, Riederer SJ, Ehman RL (1996) Magnetic resonance imaging of transverse acoustic strain waves. Magn Reson Med 36:266±274 63. Muthupillai R, Ehman RL (1996) Magnetic resonance elastography. Nat Med 2:601±603 64. Kruse SA, Smith JA, Lawrence AJ, Dresner MA, Manduca A, Greenleaf JF, Ehman RL (2000) Tissue characterization using magnetic resonance elastography: preliminary results. Phys Med Biol 45:1579±1590 65. Manduca A, Oliphant TE, Dresner MA, Mahowald JL, Kruse SA, Amromin E, Felmlee JP, Greenleaf JF, Ehman RL (2001) Magnetic resonance elastography: non-invasive mapping of tissue elasticity. Med Image Anal 5:237±254 66. McKnight AL, Kugel JL, Rossman PJ, Manduca A, Hartmann LC, Ehman RL (2002) MR elastography of breast cancer: preliminary results. Am J Roentgenol 178:1411±1417 67. Lorenzen J, Sinkus R, Lorenzen M, Dargatz M, Leussler C, Roschmann P, Adam G (2002) MR elastography of the breast: preliminary clinical results. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 174:830±834

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68. McCracken PJ, Manduca A, Felmlee JP, Ehman RL (2002) Mechanical transient-based MR elastography. Proc Intl Soc Mag Reson Med 10 69. Dresner MA, Rose GH, Rossman PJ, Muthupillai R, Manduca A, Ehman RL (2001) Magnetic resonance elastography of skeletal muscle. J Magn Reson Imaging 13:269±276 70. Jenkyn TR, Kaufman KR, An KN, Ehman RL (2002) Change in relaxed muscle stiffness due to joint positioning measured in vivo using magnetic resonance elastography. Proc Intl Soc Magn Reson Med 10 71. Sack I, Tolxdorff J, Bernarding T, Braun J (2002) Simulation of MR elastography wave images measured in the biceps brachii. Proc Intl Soc Magn Reson Med 10 72. Uffmann, Mateiescu S, Quick HH, Lado ME (2002) In vivo determination of biceps elasticity with MR elastography. Proc Intl Soc Magn Reson Med 10 73. Budinger TF, Benaron DA, Koretsky AP (1999) Imaging transgenic animals. Annu Rev Biomed Eng 1:611±648 74. Behar L, den Hollander JA, Stromski ME, Ogino T, Shulman RG, Petroff OA, Prichard JW (1983) High-resolution 1H nuclear magnetic resonance study of cerebral hypoxia in vivo. Proc Natl Acad Sci USA 80:4945±4948 75. Berkelbach, van der Sprenkel JW, Luyten PR, van Rijen PC, Tulleken CA, den Hollander JA (1988) Cerebral lactate detected by regional proton magnetic resonance spectroscopy in a patient with cerebral infarction. Stroke 19:1556± 1560 76. Fenstermacher I, Narayana PA (1990) Serial proton magnetic resonance spectroscopy of ischemic brain injury in humans. Invest Radiol 25:1034±1039 77. Duijn JH, Matson GB, Maudsley AA, Hugg JW, Weiner MW (1992) Human brain infarction: proton MR spectroscopy. Radiology 183:711±718 78. Pan JW, Hamm JR, Hetherington HP, Rothman DL, Shulman RG (1991) Correlation of lactate and pH in human skeletal muscle after exercise by 1H NMR. Magn Reson Med 20:57±65 79. Shen D, Gregory CD, Dawson MJ (1996) Observation and quantitation of lactate in oxidative and glycolytic fibers of skeletal muscles. Magn Reson Med 36:30±38 80. Asllani I, Shankland E, Pratum T, Kushmerick M (1999), Anisotropic orientation of lactate in skeletal muscle observed by dipolar coupling in (1)H NMR spectroscopy. J Magn Reson 139:213±224 81. Chatham IC, Blackband SJ (2001) Nuclear magnetic resonance spectroscopy and imaging in animal research. ILAR J 42:189±208

Microelectrodes and Biocompatible Sensors for Skin pO2 Measurements

19

Wen Wang, Pankaj Vadgama

Introduction The potential of monitoring oxygen (O2) levels on a continuous real-time basis gives the opportunity to both assess dynamic fluctuations and make a predictive assessment of O2 trends in any particular localized environment [1]. Electrochemical and optical (fibre-optic) sensors provide a near ideal means of localized tissue monitoring other than totally non-invasive methods such as the near-infrared monitoring of the inter-converting Hb/ HbO2 chromophore pair pioneered by Jæbsis [2] and referred to in Chap. 17. In both electrochemical and optical sensors, a direct interfacial reaction takes place, which can be conveniently amplified and translated into a continuous electrical output using systems suitable for near-patient use. A key capability is that of virtually reagentless measurement in an optically opaque tissue matrix ± ideal for subcutaneous measurement. With the advent of miniaturization techniques, including those adapted from the microelectronics industry, ethically acceptable, clinically invasive monitoring becomes feasible. Application criteria include sensitivity, selectivity, stability, biocompatibility, reliability and overall safety. Undoubtedly, an important route to overcoming many of these problems was to retain sensors behind permselective membranes and appropriate encapsulants [3]. Interfacing with appropriate polymer membrane coverings has permitted the operation of many sensors independently of solution variables presented by the in vivo milieu.

Electrochemical Monitoring The polarographic principle of electrochemical O2 reduction at a noble metal working electrode polarized at approximately ±0.65V vs. Ag/AgCl is well established. However, in the Clark electrode design [4], an O2-permeable membrane separates an entire (two-electrode) electrochemical cell from the unmodified, undiluted biological matrix. This methodology has been the mainstay of implantable O2 sensors. The membrane, typically made of PTFE, has a crucial role in restricting O2 permeability sufficiently to limit evolved diffusion gradients to within the physical confines of the mem-

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Microelectrodes and Biocompatible Sensors for Skin pO2 Measurements Fig. 19.1. Polarographic `stab' electrode for tissue pO2 monitoring (after [5])

brane material itself, so avoiding further impact of sample O2 permeability variation due to sample matrix alteration ± a particular consideration when devices are implanted within tissue. For tissue monitoring such probes need to be of reduced diameter, and have tended to be fragile and difficult to construct. Van der Kleij and de Koning [5] constructed a needle electrode (Fig. 19.1) utilizing a platinum wire cathode of 5 lm diameter insulated in glass, and incorporated into a spinal needle of 0.5 mm bore. Here, to avoid a separate reference electrode, the stainless steel was used as the anode [6]. The key feature is that the working electrode is protected and O2 diffusion gradients are internalized within the fluid column of the recess. This ensures that, as with a low-permeability covering membrane, the diffusion field extending into the tissue matrix is negligible. This means that the O2 flux to the working electrode is independent of sample matrix and only reflects local PO2. Schneiderman and Goldstick [8] examined the influence of recess dimensions and aspect ratios to determine the influence of externalized diffusion fields around the electrode tip. Undoubtedly, a recessed tip structure is able to stabilize O2 measurements and to some extend protect the working electrode surface from biofouling. Indeed, Davies and Brink [8] had previously concluded that recessed-tip electrodes and intermittent voltage pulses to the working electrode were the only means of obtaining reliable pO2 measurements in tissue. Interest in tissue pO2 has increased in view of the radiosensitization of O2 and the value of relating O2 tension to radiation dose. There was also the realization that steep O2 gradients exist in tissue, and that it was necessary to understand the three-dimensional profile of pO2, particularly in relation to the microcirculation. The additional advantage of using a microelectrode is the limit to the competition for O2 consumption with cells in the immediate environment of the device. Silver [9] discussed the relevant issues and concluded that intermittent sweep potentials applied to the working electrodes reduced O2 consumption and minimized equilibration time, thereby reducing artefactual influences on tissue and facilitating rap-

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id clinical measurement. With the advent of microfabrication, miniaturized planar O2 electrodes have been produced. In one example, Suzuki [10] produced a 350-lm-depth silicon structure which featured anisotropically etched V-grooves that contained electrolyte and whose surfaces included a cathode (working electrode) and an anode. This internal micro-reaction chamber for the polarographic reduction of O2 was bounded by a gaspermeable membrane based on a negative photoresist. The membrane provided for electrochemical stability within the device, protected the sensing surface from biofouling and controlled O2 flux. However, such a Clark-type electrode construction, whilst having advantages for bio-interfacing, does complicate microdevice construction and scale up of production. A commercially available medical system is that marketed by Eppendorf. This microelectrode comprises a recessed gold±platinum wire combination in an insulating glass needle, in turn housed within a 300-lm o.d. protective needle. The recessed gold surface is membrane protected, and so approximates to the desired structure for tissue measurements. Automated sub-millimetre advance and retraction within the tissue allows multiple location measurements, but with post-retraction measurement the problems of tissue compression are obviated. Tama-Dasu et al. [11] related the putative O2 consumption of the electrode tip to simulated tissue measurements by differentially weighting O2 at different 3-D locations in tissue. They concluded that, for limited measuring times, O2 transport from more distant locations will be restricted; therefore, what the electrode provides is an ªaveragedº approximation of the time value of clinical validity, which is not appropriate for data input into more formal tissue-modelling procedures. By contrast, direct, free quantitative consumption of O2 by a large electrode applied to the liver surface (Ag working electrode, diameter 3 mm) was used intentionally by Seifalian et al. [12] to measure perfusion-driven delivery of O2 to the liver. The electrode had a highly permeable covering membrane. Such a construction could, perhaps, provide a measure of changes to the cutaneous circulation. However, for non-invasive monitoring of the skin, the conventional approach has been that of the heated transcutaneous pO2 electrode [13]. Here, heating permeabilizes the thick outer stratum corneum of skin to allow rapid O2 diffusion. The route taken involves numerous biological barriers, but heating stabilizes, and also arterializes, the dermal capillary bed. Whilst accuracy is compromised in thicker adult skin relative to neonatal skin, where the electrode has seen most application, Stçcker et al. [14] used such an electrode to measure O2 consumption by the skin in patients with chronic venous skin lesions. They measured transcutaneous pO2 reduction after arresting arterial O2 supply. Using the pO2 solubility coefficient for skin, they were then able to determine skin O2 consumption differences between patients with and without venous ulceration. Evident lowering of transcutaneous pO2 was judged to be a late-onset phenomenon. A more distributive assessment of tissue O2, short of a 3-D O2 map is to create a pO2 distribution profile. Using the Eppendorf short penetration/ retraction procedure, Nozue et al. [15] undertook a thorough evaluation of

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pO2 distribution in defined turnover volumes. There was semi-quantitative agreement between laboratories concerning the turnover hypoxic zones, and such a methodology could also enable more quantitative assessment of skin hypoxia.

Fibre-Optic O2 Sensors Optically based O2 sensors almost all exploit the interference of O2 on the quantum yield and/or lifetime of excited fluorescent or phosphorescent molecules. Specially formulated dyes with high-efficiency O2 quenching have allowed for the fabrication of miniaturized fibre-optic probes able to monitor pO2 over the medically important range [16]. The reversible, dynamic quenching occurs through the formation of an O2 charge±transfer complex on collision of O2 with the excited fluorophore which, in turn, leads to non-radiative transfer to the ground state. For the purposes of invasive, transcutaneous monitoring, it is optimal to attach the reagent to the fibre-optic tip. The fibre-optic probe of Peterson and Vurek [17] translated the principle of O2-quenched fluorescence of a dye to a practical solution (Fig. 19.2). The advantage of this approach is that the electrode truly approaches equilibrium, and so does not consume O2 as such, there is no dependence on external tissue flux, and so the device is independent of sample properties. Moreover, there is no external electrical interference. A simple probe can be used, without the need for a reference electrode. Flexibility of fibre-optics is certainly a disadvantage with respect to implantation, but if, for example, a narrow needle (Fig. 19.2) or indeed a retractable needle is used, then insertion is possible. The remaining device is a tissuecompliant, flexible probe that is less liable to induce pain, tissue irritation or ongoing trauma. There is interest, now, in the development of microscale optical probes with tip diameters in the range of 10±30 lm. To further create compact systems, the O2-quenched indicator requires activation by a light-emitting diode (LED) and a luminescent lifetime of greater than 1 ls [18]. Ruthenium (II) tris(dipyridye)-type organometallic complexes have proved attractive for this reason; they can have fluorescence lifetimes up to 5.0 ls,

Fig. 19.2. Fibre-optic O2 sensor based on dye fluorescence quenching exploitation of microporous membrane to retain perylene dibutyrate dye (after [49])

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i.e. efficiently quenched by O2, excitation wavelengths (approximately 460 nm) suited to blue LEDs and demonstrate large stokes shifts (emission maxima *600 nm). Variants on the organometallic model include ruthenium and platinum phosphorescent complexes with porphyrins, which have proved attractive for microelectrodes because of strong phosphorescence, the ease of polymer matrix entrapment and high phosphorescence yields [19]. For microelectrode fabrication, the simple basic rules include [18]: z An indicator of activity per unit area z Mechanical integrity with strong adherence to the optical interface z A higher degree of rigidity to the immobilizing matrices than for conventional, larger electrodes (viz. PMMA, sol gels). With optimization of the retaining polymer matrix, it is possible to create multi-element arrays [20] not only for topological and spatial resolution, but to permit more sophisticated multivariate analysis for self-correction and measurement verification during use. Conversion to a practical structure was reported by Holst et al. [21], who formed multiple flame-tapered optode tips of 20±30 lm (Fig. 19.3) and retained indicator within a polystyrene matrix. They used reduced lifetime of the luminescence to determine O2 quenching, thereby avoiding the effects of dye photobleaching, optical background, sample optical properties and the complicating effects of add-on optical insulation. The operational set-up utilized sinusoidal light excitation and the dye lifetime decay induced a phase delay in emitted light. Phase-angle shift allowed measurement of O2 flux over the forearm skin surface from atmospheric air using a planar dye-loaded sensor foil [22]. In these studies, cuff inflation to occlude local circulation led to a drop in superficial skin pO2 and therefore an increased air±skin pO2 gradient, facilitating pO2 uptake from the ambient air. Andrezejewski et al. [23] simplified the task of microsecond light decay processing by measuring signal amplitudes at two distinct frequencies for differentiated light modulation, readily followed by lock-in amplifiers instead of high-speed photodetectors. For long-term monitoring, photobleaching is a concern, with evidence that, as well as expected decreases in emission intensity, decay time may also be affected. Hartmann et al. [24] monitored the contributory effects of singlet O2 (produced by quenching) on photobleaching, and were able to mitigate these through co-incorporation of amine singlet O2 scavengers. The principle of fluorescence lifetime decay has been used for skin surface pO2 imaging, on the basis that multiple electrode arrays cannot provide equivalent spatial resolution. Hartmann et al. [24] developed ruthenium (II) organometallic-based O2 permeable films, and topographical lifetime images were obtained that related to spatial O2 distribution on a submillimetre scale using a CCD camera. Transparent planar O2 sensors for such imaging have been developed by Holst and Grunwald [25], who embedded ruthenium (II)-tris-4, 7-diphenyl-1, 10-phenanthroline with trimethylsilypropanesulphonate as counter-ion in PVC coated over transpar-

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Fig. 19.3. O2 microelectrode based on a tapered silicon glass fibre fixed in a glass microcapillary (after [21])

ent polyester. The advantage of the transparent construction is that pO2 distribution can be correlated directly with structural images. Future optical sensors will have greater stability and biocompatibility. However, improvements in optical characteristics such as excitation/emission maxima, air/nitrogen indicator stability, quantum yield and decay profile are likely with new indicators and better polymeric immobilization strategies [26].

Cutaneous Microcirculation The cutaneous microcirculation has a unique anatomical arrangement that accommodates different often conflicting functions, namely, the supply of nutrients, clearance of waste products and control of heat exchange [27]. The arterial supply and venous drainage to the skin are located deep in the hypodermis. They give rise to arterioles and venules to form two important plexuses in the dermis: the deeper cutaneous plexus at the junction of the hypodermis and the dermis and the superficial sub-papillary plexus just beneath the dermal papillae [28]. The sub-papillary plexus supplies the upper layer of the dermis and gives rise to a capillary loop in each dermal papilla. In the epidermis, cells produced by mitosis in the germinal layer undergo different stages of maturation and move progressively to the outer layers. The cornified layer in the outermost region of the skin consists of flattened cell remnants that are constantly shed (Fig. 19.4). The superficial layer of the skin is the region between the sub-papillary plexus and the surface of the skin. While there is recent evidence that O2 entering the skin from the atmosphere may satisfy the O2 requirements of the cells in these areas [29], there has been no investigation of counter-current-arranged capillary loops in the papilla and their significance to O2 delivery to the epidermis [30, 31]. While there have been many studies on mechanisms of O2 transport within tissues, including the skin (see reviews by Scheuplein and Blank [32]; Popel [33] and Pittman [34]), much of the experimental work on skin has been limited to estimates of mean tissue

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Microelectrodes for pO2 Distribution in Superficial Layers of Human Skin

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Fig. 19.4. Diagrammatic representation of the outer layers of the human skin, consisting of the dermal papillae and the epidermis. The papillary plexus gives rise to a single papillary loop in each dermal papilla. Cells in the epidermis undergo maturation from the germinal layer adjacent to the dermal papillae to the stratum corneum in the outermost layer, which is shed continuously

pO2 from measurements of transcutaneous pO2 or has used needle electrodes that were large relative to the dermal papillae [35±39]. There have been few attempts to relate the spatial distribution of pO2 to the arrangement of the cutaneous microcirculation using small, O2-sensitive microelectrodes [1]. This study examined the distribution of pO2 in the epidermis and dermal papillae in the skin of the finger nailfolds of healthy human subjects, when entry of O2 from the atmosphere has been minimized by covering the skin surface with oil. Nailfolds were chosen for easy visualization of the microvascular architecture, since the cornified epithelium is thin and the most distal papillary loops lie almost parallel to the skin surface. The authors have also investigated changes in tissue pO2 when the blood flow in adjacent capillaries is stopped and later re-started. In this chapter, we draw attention to this study in detail.

Microelectrodes for pO2 Distribution in Superficial Layers of Human Skin In studies using small microelectrodes, pO2 measurements are limited to the superficial layers of the skin, since the penetration of deeper skin and underlying muscle requires much stronger, hence bigger, electrodes. O2sensitive microelectrodes were made using platinum±iridium wire, of 25 lm diameter, which was electrochemically etched to a slender profile with tip diameter less than 1 lm in saturated nitric acid solution. It was

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soldered to a conducting wire and was then fixed inside a 1.5-mm standard-walled glass pipette using the epoxy resin Araldite [40]. The glass pipette was mounted on a micropipette puller, which pulled the electrode to the desired tip size and profile and ensured that the glass sealed around the top of the wire. The tip of the electrode was bevelled using a micropipette grinder to enable easy tissue penetration. The surface of the metal electrodes was cleaned by sonication in distilled deionized water and was coated with Nafion perfluorinated ion exchange resin. To investigate the effects of occluding the local microcirculation on the tissue pO2, some electrodes were made with a special u-shaped tip by repeated heating of the tip of the pulled electrode and fusing a small glass bead to the shaft approximately 200 lm above the tip. These microelectrodes behaved identically to conventional ones as they penetrated the tissue up to the depth at which the bulbous region of the glass shield came into contact with the skin surface. Further advance of the electrode compressed the underlying tissue, occluding the local microcirculation. This provided a convenient method for investigating the transient effects of microcirculatory arrest upon tissue pO2. It is not uncommon for electrodes of this size to break during experiments, often as a result of the unconscious movements of the finger. Penetration of skin and advance of electrodes in tissue were also occasionally responsible. Prior to the experiment, the stratum corneum was removed for easier electrode penetration using adhesive tape. The reference electrode (Ag/AgCl ECG electrode) was placed on the skin near the finger. The microelectrode was mounted on a 3-D remote hydraulic micromanipulator (Narishige, Japan) which, in turn, was mounted on a tri-axial coarse micromanipulator (Narishige, Japan). Both the working and the reference electrodes were connected to the potentiostat (CV37; BAS). Currents from the potentiostat at ±0.75 V vs Ag/AgCl were recorded on a chart recorder. Skin was illuminated using a cool light source. Paraffin oil was superfused over the finger to minimize transport of O2 from the air and to reduce light reflections from the surface of the skin. A Wild M10 stereomicroscope (Leica) was used to visualize nailfold capillaries and flows in these capillaries. Although blood flow velocity was not estimated, the red blood cells were used as markers to indicate flow conditions, namely whether the blood flow had partially or fully stopped or was reinstated. The coarse micromanipulator was used to position an electrode just above the site of the measurement, while the remote hydraulic micromanipulator was used for the penetration of the skin and movement of the electrode within the tissue. In all measurements, the O2 partial pressure of the air was considered to be 160 mmHg at sea level and at room temperature.

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Spatial Variations of pO2 in Superficial Layers of Skin

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Spatial Variations of pO2 in Superficial Layers of Skin Mean values for the spatial variations of the pO2 with depth in the outer skin are presented in Fig. 19.5. In Fig. 19.5 a, mean pO2 has been plotted for the superficial (5±10 lm), the middle (45±65 lm) and the deep (100± 120 lm) regions in the dermal papillae of finger nailfolds. It is seen that the pO2 increases with depth from the surface of the skin to the dermis. With paraffin oil applied, pO2 was lowest at the surface of the skin. In the superficial region of the skin, pO2 is approximately 8.0Ô3.2 mmHg (n = 6). The value increases to 24.0Ô6.4 mmHg (n = 8) in dermal papillae, and at the depth just above the sub-papillary plexus, pO2 is approximately

Fig. 19.5. Spatial variations of pO2 in outer layers of nailfold skin. a Mean values for pO2 at depths of 5±10 lm (surface), 45±65 lm (middle) and 100±120 lm (deep) in all areas of nailfold skin. The pO2 at the surface and in the deep regions differ very significantly from those in the middle region (p < 0.00005 and p < 0.005 respectively). b Mean values for pO2 with depth in tissue close to the axis of the capillary loops of the papillae. While pO2 at the tip differs significantly from its value at the base (p < 0.01), the gradient is too small for significant differences to be detected between the pO2 of the tissues around the middle of the capillary loops and the pO2 at the tip and the base

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35.2Ô8.0 mmHg (n = 9). Analysis of variance (ANOVA) of the three sets of data showed highly statistically significant differences. Two-tailed Student's t-test yielded a p value of 0.005 or lower. The pO2 value was also measured along the axis of papillary loops. These measurements were carried out with the microelectrode tip at points in the tissue that were close to the most distal (and hence most horizontal) capillary loops of the nailfold. As shown in Fig. 19.5 b, pO2 generally decreased from the base to the tip of the papillary loop. At the base of the loop, pO2 is approximately 40Ô4.8 mmHg (n = 6), decreasing to 35.2 Ô 3.2 mmHg in the middle (n = 6) and 30.4 Ô 5.2 mmHg near the tip of the loop (n = 6). ANOVA of the three data sets confirmed statistically significant variations in the pO2 along the axis of papillary loops. Student's t-test revealed that p < 0.01 between data at the base and the tip of the papillary loop; however, the differences between values at the base and the middle of the papillary loop, and between those at the middle and the tip of the loop, were not statistically significant (p > 0.05).

Temporal Variations in pO2 Following Micro-Occlusion Special }-shaped electrodes were used to investigate the transient changes in skin pO2 when the microcirculation is suddenly arrested and restored. In experiments where flow in the capillary and underlying sub-papillary plexus was either reduced or stopped, pO2 in dermis decreased with the time in all cases by 16±24 mmHg. In several cases, there were initial shortlived increases in pO2. These were most probably caused by interference from the slight movement of the electrode in the tissue. New steady values in pO2 were reached within 30±60 s following alterations in capillary flow. The dynamic changes in pO2 with time can be described by a single exponential decay function: P ˆ a exp… t=s† ‡ b

…19:1†

where P is the value of pO2 during the transient, s is the time constant, a represents the difference between the initial and final values of pO2 and b is the final value of pO2. After a period of microcirculatory arrest lasting between 1 min and 5 min, flow was restored. The increase in pO2 can be described by a similar single exponential function: P ˆ a … t=s † ‡ b

…19:2†

where s* is the time constant for the exponential rise and a* and b* represent the range and the initial value of pO2. Time constants for the exponential decays (ischaemia) and rises (reperfusion) in pO2 are shown in Fig. 19.6 a. The mean time constant for the decay (8.44 Ô 1.55) was significantly higher than the corresponding value for

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Fig. 19.6. Temporal characteristics in localized microvessel occlusion and reperfusion. a Time constants of mono-exponential decays of the pO2 during microvessel occlusion differed significantly to those of exponential rises in reperfusion (p < 0.0005). b Mean values for pO2 before, during and after local reduction in blood flow. After reduction in blood flow, mean pO2 was significantly reduced (p < 0.003). After restoration of flow, pO2 was increased to levels significantly above the initial control values (p < 0.05)

the increase (4.75 Ô 0.82), a difference which was statistically significant (p < 0.001). Figure 19.6 b shows the steady values of the pO2 following ischaemia after reperfusion and the values prior to arrest of the microcirculation (the control state). There was a significant decrease in the pO2 following arrest of the local microcirculation. The pO2 is reduced by an absolute value of 16 mmHg, representing a 45% decrease. When blood flow is restored pO2 increases to 43.2 Ô 6.4 mmHg, an approximately 125% increase over the ischaemic state value, which in turn is 23% greater than the control. Differences in pO2 between ischaemia and control, and between ischaemia and reperfusion, were highly significant (p < 0.001). There was also significant difference between pO2 values in control and in reperfusion (p < 0.05).

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O2 Supply to Skin The study using small microelectrodes showed that when the skin of the human finger nailfold is covered with paraffin oil, the pO2 in the tissue increases with depth from values close to zero at the surface to about 40±50 mmHg close to the sub-papillary plexus. These agree with previous experimental and theoretical estimates of pO2 in this part of the skin [38, 41±43]. An increase in pO2 with depth would be predicted if all O2 is delivered to the papillary dermis and epidermis from the sub-papillary plexus. Under physiological conditions, however, O2 can enter the outermost layers of the skin from the atmosphere, and recent measurements by Stçcker et al. [29] have shown that this influx may be as much as 5.3 ml cm±2 min±1, sufficient to meet the needs of the epidermis. Under these conditions the pO2 profile with increasing depth beneath the skin surface might be expected to differ considerably from that reported by Wang et al. [1]. Although there is now strong evidence that O2 can enter the skin from the atmosphere, the latter study demonstrates that when this is prevented, the O2 supply to the epidermis and superficial dermis can be maintained by the papillary microcirculation [1]. There is also a suggestion that the papillary microcirculation is regulated to meet the O2 requirements of the tissue at a very local level.

Effects of Localized Ischaemia±Reperfusion Wang et al. [1] reported that when flow was stopped, pO2 fell exponentially from a mean value of *38 mmHg to *21 mmHg with a mean time constant of just less than 8.5 s. In six of their seven experiments, the recording electrode was close to the sub-papillary plexus, as indicated by relatively high pre-occlusion values of the pO2, i.e. in the range of 40 mmHg. When flow was stopped in vessels close to points near the base of the papillae, pO2 fell to 20±24 mmHg, indicating that the supply of O2 could be maintained, presumably by diffusion from surrounding vessels where microvascular flow was undisturbed. In one of their experiments, however, the electrode tip was at an intermediate depth in the tissue, where the arrest of local capillary flow brought pO2 close to zero. This one observation strongly suggests that O2 supply to the outer papillary dermis and epidermis is absolutely dependent on flow in the closest vessels. The exponential decline in pO2 when flow is stopped would be consistent with the discharge of O2 from stores in the tissue. The most likely site of these O2 stores is the haemoglobin of the red cells in the capillaries where flow has been arrested. The oxyhaemoglobin dissociation curve is approximately linear over the range of pO2 between 15 mmHg and 40 mmHg, and the unloading of O2 over this range might be expected to approximate to that of a single exponential function. The rise of pO2 to a new steady state as flow is restored is determined by the rate at which the pO2 in capillaries is returned to their pre-occlu-

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sion values. This is primarily dependent on the blood flow velocity in the reperfused capillaries. If the tissue at the tip of the microelectrode is considered to be principally supplied by O2 from a point along an adjacent capillary, the rate at which capillary pO2 rises at this point will depend on how rapidly blood with a higher pO2 reaches that point and how much the blood pO2 falls between leaving the arteries and arriving at this point. Providing the O2 consumption of the tissue remains constant, the extraction (i.e. the O2 lost per unit volume of blood) should be largely dependent on the blood flow. If the post-occlusion flow is greater than in the pre-occlusion state, not only will the pO2 rise rapidly, but it should rise above its initial level. The tissue pO2 should then remain above its initial value for as long as the flow is elevated. This was observed in the experimental study. When blood flow is restored, tissue pO2 rises to a value that is 23% higher than its pre-occlusion value. This is consistent with either a decrease in tissue O2 consumption or a significant degree of reactive hyperaemia. Assuming that tissue O2 consumption is the same as in the pre-occlusion state, the 23% increase in pO2 is equivalent to an increase in O2 saturation in the blood of the nearest capillaries from 70% to 85%. If the saturation of the arterial blood is 95%, the increase in blood flow equivalent to the rise in tissue pO2 is of the order of 2.5-fold. This calculation indicates that reactive hyperaemia occurs with a high spatial resolution in skin, and this would be consistent with the very localized hyperaemic responses seen in some other tissues [44]. Although the rise in pO2 accompanying reperfusion can be described approximately by a single exponential, the data were less regular than those describing the decline in pO2 with vascular occlusion. This may represent fluctuations in blood flow velocity or red cell flux with the restoration in flow [45].

Future Prospects The electrochemical and fibre-optic devices described in this chapter are best regarded as semi-implantable, minimally invasive devices. They have the potential to provide localized information on, at least, approximate pO2 in prespecified skin and skin ulcer microenvironments. There are two major developments likely to improve spatial discrimination and reliability. First, evolving microfabrication techniques will allow robust probe structures to be fabricated as arrays able to penetrate in and around the ulcer wound site, but with negligible local trauma. This `atraumatic' insertion should minimize local tissue reaction with less tissue disruption. Devices will then become truly minimally invasive and yet have a high sensor/interrogation density, with features equivalent to a chemically reactive ªVelcroº. A further advantage will be a high level of sensor redundancy, allowing for greater confidence in the measurements. With appropriate additional microinjection capability along such arrays, it can be envisaged that pharmacologically active agents may be injected locally, e.g. vasodilators to monitor localized circulatory re-

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activity as a possible dynamic indicator of tissue integrity. The second key advance will come from materials science. Already, membrane technology has improved the stability and biocompatibility of biosensors. Further advances should help to further reduce the inevitable drift that O2 sensors suffer due to surface fouling and contamination [46]. Other possible advances will exploit tissue-embedded optical nanoprobes coated with, for example, O2-reactive dyes, so developing the recent concept of probes encapsulated by biologically localized embedding, socalled PEBBLE sensors [47]. Whist such micrometre-scale spheroids have allowed distributed sensing in vitro, the correct formulation may enable safe in vivo use; moreover, with near-infrared active dyes, interrogation of deeper skin layers becomes possible. The ultimate goal must be sensorbased feedback on a real-time basis so that local pO2, a key surrogate of tissue metabolic status, can be used to optimize therapeutic regimens for pressure ulcers. Acknowledgement. The authors thank Ms Monika Schoenleber for her help in preparing Figs. 19.1±19.3.

References 1. Wang W, Winlove CP, Michel CC (2003) Oxygen partial pressure in outer layers of skin of human finger nail folds. J Physiol 549 (3):855±863 2. Jæbsis FF (1977) Non invasive infrared monitoring of cerebral and myocardial oxygen insufficiency and circulatory parameters. Science 198:1264±1266 3. McDonnell MB, Vadgama P (1989) Membranes: separation principles and sensing. In: JDR Thomas (ed) Selective electrode reviews, vol 11. Pergamon Press, New York, pp 17±67 4. Clark LC (1956) Monitor and control of blood and tissue oxygen tension. Trans Am Soc Inter Organs 2:41±46 5. van der Kleij JA, de Koning J (1981) Tissue oxygen electrode for routine clinical application. In: Limmich HP (ed) Monitoring of vital parameters during extracorporeal circulation. Karger, Basel, p 95 6. Whalen WJ, Spande JI (1980) A hypodermic needle pO2 electrode. J Appl Physiol 48:186±187 7. Schneiderman G, Goldstick TK (1978) Oxygen electrode design criteria and performance characteristics recessed cathode. J Appl Physiol 45:145±154 8. Davies PW, Brink F (1942) Microelectrodes for measuring local oxygen tension. I. Animal tissues. Rev Sci Instrum 13:524±533 9. Silver IA (1986) In: Akhtar M, Lowe CR, Higgins IJ (eds) Biosensors. Proceedings of the Royal Society Discussion Meeting. The Royal Society, London 10. Suzuki H, Kojima N, Sugame A, Takei F, Ikegami K (1990) Disposable oxygen electrodes fabricated by semi conductor techniques and their application to biosensors. Sensors Actuators B1:528±532 11. Tama-Dasu I, Waites A, Dasu A, Denekamp J (2001) Theoretical simulation of oxygen tension measurement in tissues using a microelectrode. I. The response function of the electrode. Physiol Meas 22:713±725

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12. Seifalian AM, Mallett S, Piasecki C, Rolles K, Davidson BR (2000) Non-invasive measurement of hepatic oxygenation by an oxygen electrode in human orthotopic liver transplantation. Med Eng Phys 22:371±377 13. Huich A, Huch R (1976) Transcutaneous, non-invasive monitoring of pO2. Hosp Pract 6:43±52 14. Stçcker M Falkenber M, Reuthor T, Altmeger P, Lçbber DW (2000) Local oxygen content in the skin is increased in chronic venous incompetence. Microvascular Res 59:99±106 15. Nozue M, Lee F, Yuan F, Teicher B, Brizel DM, Dewhirst MW et al (1997). Interlaboratories variation of oxygen tension measurement by Eppendorf ªHistographº and comparison with hypoxic marker. J Surg Oncol 66:30±38 16. Wolfbeis OS (1991) Fiber optic chemical sensors and biosensors. CRC Press, Boca Raton, FL 17. Peterson JJ, Vurek GG (1984) Fibre-optic sensors for biomedical applications. Science 224:123 18. Kilmant I, Kçhl M, Glud RN, Holst G (1997) Optical measurement of oxygen and temperature in microscale: strategies and biological applications. Sensors Actuators B38:29±37 19. Papkovsky DP, Olah J, Troyanovsky IV, Sadovsky NA, Rumyantseva VD, Mironov AF, Yaropolov AI, Savitsky AP (1991) Phosphorescent polymer films for optical oxygen sensors. Biosensors Bioelectron 7:199±206 20. Gauglitz G, Brecht A (1997) Recent developments in optical transducers for chemical and biochemical applications. Sensors Actuators B38:1±7 21. Holst G, Glud RN, Kçhl M, Klimant I (1997) A micro-optode array for finescale measurement of oxygen distribution. Sensors Actuators B38:122±129 22. Holst GA, Kæster T, Voges E, Lçbbers DW (1995) Flox-on oxygen-flue-measuring system using a phase-modulation method to evaluate the oxygen-dependent fluorescence lifetime. Sensors Actuators B29:231±239 23. Andrzejewski D, Klimant I, Podrielska H (2002) Method of lifetime-based chemical sensing using the demodulation of the luminescence signal. Sensors Actuators B84:160±166 24. Hartmann P, Ziegler W, Holst G, Lçbbers DW (1997) Oxygen flux fluorescence lifetime imaging. Sensors Actuators B38:110±115 25. Holst G, Grunwald B (2001) Luminescence lifetime imaging with transparent oxygen optodes. Sensors Actuators B74:78±90 26. Papkovsky BD (1995) New oxygen sensors and their application to biosensors. Sensors Actuators, B29:213±218 27. Wheater PR, Burkitt HG, Daniels VG (1979) Functional histology. Churchill Livingstone, New York, pp 116±127 28. Braverman IM (1997) The cutaneous microcirculation: ultrastructure and microanatomical organization. Microcirculation 4:329±340 29. Stçcker M, Struk A, Altmeyer P, Herde M, Baumgårtl H, Lçbbers DW (2002) The cutaneous uptake of atmospheric oxygen contributes significantly to the oxygen supply of human dermis and epidermis. J Physiol 538 (3):985±994 30. Wang W, Parker KH, Michel CC (1996) Theoretical studies of steady state transcapillary exchange in countercurrent systems. Microcirculation 3:301± 311 31. Wang W (2000) A critical parameter for transcapillary exchange of small solutes in countercurrent systems. J Biomech 33:433±441 32. Scheuplein RJ, Blank IH (1971) Permeability of the skin. Physiol Rev 51 (4):702±747

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33. Popel AS (1989) Theory of oxygen transport to tissue. Crit Rev Biomed Eng 17:257±321 34. Pittman R (1995) Influence of microvascular architecture on oxygen exchange in skeletal muscle. Microcirculation 2:1±18 35. Evans NTS, Naylor PFD (1966/7) Steady states of oxygen tension in human dermis. Respir Physiol 2:46±60 36. Spence VA, Walker WF (1976) Measurement of oxygen tension in human skin. Med Biol Eng 14:159±165 37. Lçbbers DW (1987) Theory and development of trans-cutaneous oxygen pressure measurement. Int Anesthesiol Clin 25 (3):31±65 38. Jaszczak P (1991) Skin oxygen tension, skin oxygen consumption and skin blood flow measured by a tc-pO2 electrode. Acta Physiol Scand 143:53±57 39. Harrison D, Lçbbers D, Baumgårtl H, Stoerb C, Rapp S, Altmeyer P, Stçcker M (2002) Capillary blood flow and cutaneous uptake of oxygen from the atmosphere. In: Kessler MD, Mueller GJ (eds) Functional monitoring and drug tissue interaction. Proc SPIE 4623:195±205 40. Winlove CP, O'Hare D (1993) Electrochemical method in physiology. Curr Topics Electrochem 2:345±361 41. Grossmann U (1982) Simulation of combined transfer of oxygen and heat through the skin using a capillary-loop model. Math Biosci 61:205±236 42. Baumgårtl H, Ehrly AM, Saeger-Lorenz K, Lubbers DW (1987) Initial results of intracutaneous measurement of PO2 profiles. In: Ehrly AM, Hauss J, Huch R (eds) Clinical oxygen pressure measurement. Springer, Berlin Heidelberg New York, pp 121±128 43. Stçcker M, Altmeyer P, Struk A, Hoffmann K, Schulze L, Rochling A, Lçbbers DW (2000a) The transepidermal oxygen flux from the environment is in balance with the capillary oxygen supply. J Invest Dermatol 114:533±540 44. Burton KS, Johnson PC (1972) Reactive hyperemia in individual capillaries of skeletal muscle. Am J Physiol 223:517±524 45. Johnson PC, Wayland H (1967) Regulation of blood flow in single capillaries. Am J Physiol 212:1405±1415 46. Reddy SM, Vadgama P (1997) Membranes to improve amperometric sensor characteristics. In: Kress-Rogers E (ed) Handbook of biosensors and electronic noses: medicine, food, and the environment. CRC Press, Boca Raton, FL, pp 111±135 47. Xu H, Aylott JW, Kopelman R, Miller TJ, Philbert MA (2001) A real-time ratiometric method for the determination of molecular oxygen inside living cells using sol-gel based spherical optical nanosensors with applications to rat C6 glioma. Anal Chem 73:4124±4133 48. Stefansson E, Peterson JI, Wang YH (1989) Intraocular oxygen tension measured with a fibre-optic sensor in normal and diabetic drugs. Am J Physiol 256:H1127±H1133

New Tissue Repair Strategies Debbie Bronneberg, Carlijn Bouten

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Abbreviations FGF EGF GM-CSF IFN IGF IL NGF PAF PDEGF PDGF TNF TGF VEGF

Fibroblast growth factor Epidermal growth factor Granulocyte±macrophage colony-stimulating factor Interferon-gamma Insulin-like growth factor Interleukin Nerve growth factor Platelet-activating factor Platelet-derived epidermal growth factor Platelet-derived growth factor Tumour necrosis factor Transforming growth factor Vascular endothelial growth factor

Introduction Pressure ulcers are localized areas of tissue breakdown in skin and/or underlying tissue [1]. They are initiated by prolonged mechanical loads applied at the interface between skin and supporting surfaces and can be aggravated by a range of predisposing factors, such as the patient's nutritional status and disease. Although pressure ulcers can occur anywhere on the body, they often develop near joints and bony protrusions, e.g. in the trochanteric, ischial, heel, and sacral areas [2]. Patients as well as the clinical and nursing staff may not immediately be aware of these developing wounds, because they often occur in bedridden, paralysed, and elderly subjects undergoing treatments for other diseases. With progression, however, the wounds become painful and more difficult to treat and may considerably affect the patient's quality of life [3]. As is pointed out repeatedly in the first section of this book, the rates of occurrence of pressure ulcers are unacceptably high and represent a burden to the community in terms of health care and money. For instance, in the United States the incidence of pressure ulcers is estimated to be 5±10% among hospitalized patients [2, 4±9], 13% among nursing home patients

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[2, 10], and up to 39% among those with spinal cord injuries [2, 11±12]. These high figures are mainly due to limited insights in pressure ulcer aetiology, and hence insufficient possibilities for pressure ulcer prevention, and have triggered substantial efforts to improve strategies for wound treatment and tissue repair. By definition pressure ulcers are chronic wounds and, therefore, have an underlying physiological impairment that affects the wound-healing process [2]. Apart from reducing interface loads, extensive treatment of these wounds is essential to promote healing of existing ulcers and to prevent development of new ulcers. Today, a wide range of wound treatment strategies is applied with varying success ratios. These strategies include debridement of necrotic tissue and creation of a moist wound-healing environment (e.g. wound dressings). With ongoing developments in biotechnology and life sciences new treatment techniques are being developed, which mainly focus on improving wound healing via biochemical stimulation of the wound bed. The most promising new treatment techniques are discussed in this chapter, such as the exogenous application of growth factors, the application of living, engineered skin grafts, grown outside the body, and the application of gene therapy.

Acute and Chronic Wounds Normal ± or acute ± wound healing proceeds through an orderly and timely sequence in which different phases can be distinguished: (1) haemostasis, (2) inflammation, (3) proliferation, and (4) maturation or remodelling [13]. No clear demarcation exists between the phases of wound healing, since tissue repair is a continuous process. Tissue injury can cause both blood vessel damage and cell death [14]. The first phases of wound healing, therefore, focus on wound sealing, removal of debris and death tissue, and reduction of infection. Haemostasis, the arrest of bleeding, is achieved by vasoconstriction and clotting [13]. The formation of a clot serves as a temporary wound shield and provides a provisional matrix over which and through which cells can migrate during the repair process [15]. Importantly, the clot also serves as a reservoir of cytokines and growth factors that are released as activated platelets within the clot degranulate (e.g. PDGF, TGF-b1, TGF-b2, PDEGF, PAF, IGF-1, fibronectin, and serotin) [15±18]. These cytokines and growth factors play an important role in the subsequent stages of wound healing. In the inflammatory phase, neutrophils and monocytes are attracted from the circulating blood to the wound site by a variety of chemotactic signals [15]. Neutrophils normally begin arriving at the wound site within minutes of injury. Their role is clearance of contaminating bacteria, as well as release of pro-inflammatory cytokines that probably serve as some of the earliest signals to activate local fibroblasts and keratinocytes [15, 19]. Unless a wound is grossly infected, the neutrophil infiltration ceases after a

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few days. Macrophages continue to accumulate at the wound site and are essential for effective wound healing [15, 20]. Their tasks include phagocytosis of any remaining pathogenic organisms and other cell and matrix debris. Once activated, macrophages release a battery of growth factors and cytokines at the wound site (e.g. FGF, EGF, VEGF, TNF-a, IL-1, and IFN-c) [15±17]. These chemical messengers also stimulate the infiltration, proliferation, and migration of fibroblasts and keratinocytes [16, 18]. The proliferative phase comprises of (1) epithelization, (2) fibroplasia, and (3) angiogenesis. [13, 21, 22]. Within hours of injury the process of epithelization takes place, and keratinocytes proliferate and migrate from hair appendages and/or wound edges to cover the exposed tissue [13]. In order to cut a path through the fibrin clot or along the interface between the clot and the healthy dermis, the leading-edge keratinocytes have to dissolve the fibrin barrier ahead of them by means of fibrinolytic enzymes [15]. Once the denuded wound surface has been covered by a monolayer of keratinocytes, epidermal migration ceases and a new stratified epidermis with underlying basal lamina is established from the margins of the wound inward [15, 23]. Attracted by cytokines and growth factors, fibroblasts migrate into the wound site within several days of injury [16]. Once activated, the fibroblasts synthesize and deposit collagen and proteoglycans (i.e. fibroplasia), which ultimately bridge the edges of the wound and give it tensile strength. Like keratinocytes, fibroblasts also release proteases that dissolve the non-viable tissue and the fibrin barrier, which facilitates the remodelling of the matrix. This matrix serves as a scaffold for angiogenesis. Angiogenesis refers to the reconstitution of blood supply to the wound. The stimulus (angiogenic polypeptides such as bFGF, VEGF, TGF-a, IGF, and PDGF) for vessel formation and growth is provided by activated macrophages and keratinocytes [16, 24]. Blood vessels bud from intact vessels and the loops of these new capillaries give the matrix a red granular appearance (i.e. granulation tissue) [13]. The remodelling phase refers to changing patterns in the deposition and organization of matrix components during wound healing. Originally the collagen fibres, which are deposited by fibroblasts, are thin and randomly oriented [16, 17]. During the remodelling phase these collagen fibres become organized into thicker bundles and, aided by proteinases, are rearranged along the stress lines of the wound [13, 16, 17]. Remodelling may last up to a year and contributes to the development of tensile strength in the wound. However, the fibres do not completely revert to their original organization (basket-weave pattern), function, or strength [16, 17]. In pathological conditions such as non-healing pressure ulcers, the normal healing sequence is impaired and the ulcers are locked into a state of chronic inflammation [25]. Mast and Schultz [26, 27] and Tarnuzzer et al. [26, 28] have postulated that this healing impairment is due to the fact that in chronic wounds, repeated trauma, ischaemia, and infection increase the levels of proinflammatory cytokines (e.g. IL-1b and TNF-a), increase the level of matrix metalloproteinases (MMPs), decrease the presence of tissue inhibitors of metalloproteinases (TIMPs), and lower the level of growth factors. Cooper et al.,

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using an enzyme-linked immunosorbent assay technique on retrieved wound fluids, showed that the levels of PDGF, bFGF, EGF and TGF-b were markedly decreased in chronic pressure ulcers compared with acute wounds [29, 30]. Recently, Diegelmann et al. demonstrated that an extensive neutrophil infiltration is responsible for the chronic inflammation characteristic of these non-healing pressure ulcers [25]. These neutrophils release significant amounts of MMPs (e.g. collagenase) that are responsible for the destruction of connective tissue matrix [25, 31, 32]. In addition, neutrophils release an enzyme called elastase that is capable of destroying important growth factors such as PDGF and TGF-a [25, 33]. Pressure ulcers further exhibit an environment containing excessive reactive oxygen species that can further damage the cells and the healing tissue [25, 34]. The Wound Healing Society's standards of care principles for pressure ulcers are pressure relief, moist wound environment, and debridement of necrotic tissue [35±36]. Stage II to IV pressure ulcers are often poorly responsive to standard treatment [37]. Because of the difficulty in treating this condition health care practitioners have often looked for an agent that will help to promote healing of these wounds. Advances in the treatment of these chronic wounds have relied heavily on concepts developed for acute wounds [38]. Wound-healing agents have traditionally included, for example, topical dressings, antimicrobial agents, disinfectants, wound cleaners, wound-debriding agents, and surgery (i.e. skin flaps) [37]. In the past few years, however, a new paradigm for the treatment of chronic wounds is emerging [38]. New therapeutic products are being developed that better address the pathogenic abnormalities of chronic wounds, such as the application of growth factors, tissue-engineered skin grafts, and gene therapy. However, healing of chronic wounds can only proceed once the inflammation is controlled [25]. To provoke an ideal response to these new therapeutics, it is important to properly prepare the wound bed first [25, 39, 40]. Therefore, ªwound-bed preparationº should always be included in the standard protocol for the treatment of pressure ulcers, as well as aggressive nutritional supplementation of all malnourished or undernourished patients [2, 41, 42].

Wound-Bed Preparation Recently, an extensive protocol for the successful treatment of pressure ulcers has been proposed [2]. An important step in this protocol is effective ªwound-bed preparationº. This treatment stage focuses on optimizing the wound bed of chronic wounds to facilitate the normal endogenous process of wound healing [38]. Wound-bed preparation is more than debridement alone. It is a very comprehensive approach aimed at reducing oedema and exudates, as well as on eliminating or reducing the bacterial burden and, importantly, correcting the abnormalities in chronic wounds that lead to impaired healing. Wound-bed preparation should be directed toward creat-

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ing a moist wound-healing environment, while facilitating granulation tissue formation (i.e., new collagen formation and angiogenesis) and decreasing the bacterial count or load in the wound [2]. New treatments can be used additionally on these wounds to promote healing.

New Treatments New wound-healing treatments aim at the biochemical stimulation of the wound bed to improve wound healing. Important new therapeutics in this category are reviewed below, such as (1) exogenous application of growth factors, (2) tissue-engineered skin grafts, and (3) gene therapy.

Growth Factors Growth factors provide many of the cellular and molecular signals necessary for normal healing, but can be deficient in pressure ulcers [26, 30, 43]. Progress in the understanding of growth factors in wound healing and the ability to synthesize adequate quantities of these factors in their pure form, using recombinant DNA technologies, has led to clinical trials evaluating their use [44, 45]. Generally, the recombinant growth factors are delivered to the wound through the application of a gel or through subcutaneous injection around the wound edges [45]. Recombinant PDGF-BB is the only growth factor preparation currently approved for clinical use in diabetic foot ulcers [13, 46±48]. In 1992, the first randomized control study on the effect of recombinant PDGF-BB on pressure ulcers was published [49, 50]. This study demonstrated an increase in the rate of wound closure of stage III and IV pressure ulcers within 4 weeks of treatment with 1 lg/cm2 PDGF-BB compared with the placebo control group and the groups treated with lower doses (0.01 lg/ cm2 and 0.1 lg/cm2 PDGF-BB) [49]. In 1999, Rees et al. examined the effect of recombinant PDGF-BB (becaplermin gel) on chronic full-thickness pressure ulcers (stage IV) in a 16-week clinical trial [44, 51]. Healing was achieved in 23% of the group treated with becaplermin gel 100 lg/g, 19% of the group treated with 300 lg/g, 3% of the group treated with 100 lg/g twice daily, and 0% of the placebo group. The negative dose±response effect, the fact that the rate of healing was considerable lower than rates reported with other standard treatments, and the finding that no ulcers healed in the placebo group make interpretations of this study problematic [44]. In another trial, Pierce et al. demonstrated that recombinant PDGFBB failed to improve the rate of complete healing of pressure ulcers, although a 15% decrease in ulcer volume was observed in the treatment group [44, 52]. Taken together, these results indicate that the efficacy of recombinant PDGF-BB in the treatment of pressure ulcers is still somewhat unclear.

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Other growth factors and cytokines, such as Il-1b, bFGF, GM-CSF, TGFb3, and NGF have also been studied for the treatment of pressure ulcers. Robson et al. studied the safety and effect of topical treatment with recombinant IL-1b in the management of stage III and IV pressure ulcers in 26 patients [53]. The use of IL-1b in this study was safe, but the dose levels tested (0.01, 0.1 and 1 lg/cm2) did not result in an improvement of the healing ratio. In another study, Robson et al. used recombinant bFGF to treat 50 patients with stage III and IV pressure ulcers in eight dosing regimes, and a trend toward faster healing was observed in six of the eight groups [44, 54]. Sequential use of recombinant growth factors has also been attempted in the treatment of pressure ulcers. In 2000, Robson et al. studied the effect of sequential GM-CSF and bFGF treatment on the healing of stage III and IV pressure ulcers [29]. A total of 61 patients were randomly assigned to receive GM-CSF for 35 days, bFGF for 35 days, sequential therapy of 10 days of GM-CSF followed by 25 days of bFGF, or placebo. The mean change in ulcer volume did not differ significantly among these four treatment groups. However, significantly more patients treated with any kind of cytokine achieved a greater than 85% decrease in ulcer volume than the placebo-controlled patients after 35 days. Furthermore, treatment with bFGF alone showed the best results in this study. In 2001, Hirshberg et al. studied the effect of recombinant TGF-b3 in the treatment of pressure ulcers [55]. The findings of this study indicate that the topical application of TGF-b3 is safe and is very effective at the earliest stages of therapy. At the termination of the study (16 weeks), however, no significant difference was observed in the healing rate among the three treatment groups (1 lg/ cm2 and 2.5 lg/cm2 TGF-b3 and placebo control). In 2003, Landi et al. attempted to determine whether recombinant NGF is an effective treatment for patients with severe pressure ulcers [44, 56]. In this study, 18 patients with pressure ulcers of the foot were randomly assigned to receive topical NGF for 6 weeks and were compared with 18 patients that received a topical placebo. After 6 weeks of treatment the average reduction in ulcer area was significantly greater in the NGF treatment group than in the placebo control group. This finding indicates that topical treatment with NGF may be an effective therapy for patients with severe pressure ulcers. Recently, Thomas indicated that the data of this study might be somewhat limited due to the study design [44]. First, only pressure ulcers of the foot were studied, which does not limit the validity of the results but makes it difficult to extrapolate them to the treatment of pressure ulcers at other locations. Second, studies in which the healing rate of the control group is very poor should always be interpreted with caution, as part of the difference between the two treatment groups may be caused by failure of treatment in the placebo control group. Since their introduction in wound healing, the prospects of topical recombinant growth factors as a new treatment for pressure ulcers were high, as preclinical studies showed very promising outcomes [38]. In contrast, the outcome of the clinical trials has been slightly disappointing. A number of explanations can be given for the limited success, and most

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probably all of them apply. First, it has been hypothesized that the dosage and mode of delivery of topically applied growth factors may have been wrong [29, 38, 57, 58]. Therefore, better insights into the effects and working pathways of growth factors in healing wounds are required. Second, topically applied growth factors could have been lost by the aggressive action of neutrophil-derived enzymes (proteases) such as elastase in pressure ulcers [25, 33]. In future, therefore, strategies need to be explored to down-regulate the neutrophil infiltration and also inhibit or neutralize the host of destructive proteases released from these powerful inflammatory cells [59, 60]. One way to tackle this problem is by effective ªwound-bed preparationº before treatment with the growth factor being tested in the clinical trials.

Tissue-Engineered Skin Grafts A current management option for non-healing pressure ulcers is surgical repair using autologous (i.e. obtained from the patient) skin flaps. Disadvantages of these skin flaps are the requirement for (large) skin biopsies and the additional donor-site wound complications, including delayed healing, scarring, pain and risk of infection [61, 62]. Tissue-engineered skin grafts can be ideal substitutes for these skin flaps. The term ªtissue engineeringª was adopted by the Washington National Science Foundation bioengineering panel meeting in 1987 [63, 64]. It refers to the application of the principles and methods of engineering and the life sciences toward the development of biological substitutes to restore, maintain, or improve function [64]. However, the essence of tissue engineering is the use of living cells together with natural or synthetic extracellular matrix components. Currently, skin products made of (1) only extracellular matrix materials, (2) mainly cells (e.g. keratinocytes and/or fibroblasts), or (3) a combination of cells and matrices have all been referred to as tissue-engineered skin. The development of tissue-engineered skin grafts has been triggered by advances in research that have focused on cell culture and the cryopreservation of living cells. A fundamental advance was made in 1975, when Rheinwald et al. successfully grew human epidermal keratinocytes for the first time in serial culture with fibroblasts [65]. The use of tissue-engineered skin grafts holds the promise of direct wound closure, while actively influencing and controlling the wound environment. The incorporation of cells in these grafts, which are able to secrete their own growth factors and other mediators of wound healing, might strongly improve the wound-healing process. A wide range of tissue-engineered skin grafts is commercially available today, some of which are already used as therapeutic products for the treatment of patients with burns and chronic wounds (e.g. venous and diabetic ulcers). These skin grafts can be broadly categorized into epidermal grafts, dermal grafts, and composite grafts, depending on the type and number of cultured

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skin layers. Apart from the type of skin layer, these products mostly differ in respect of the source of the cells and extracellular matrix (i.e. autologous, obtained from the patient; allogenic, obtained from a human donor; xenogenic, obtained from an animal donor), culture conditions, shelf life, and costs. Autologous skin grafts, which require a small biopsy from the patient's skin, seem the most ideal skin grafts. However, only few autologous skin grafts are commercially available today, because they cannot meet the requirement of immediate ªoff-the-shelf º availability. In general it takes a couple of weeks to develop a skin graft, so autologous skin grafts cannot be used for direct wound treatment. Therefore, most skin grafts consist of allogenic and/or xenogenic donor material. Disadvantages of using non-autologous donor material are the risks of disease transmission and graft rejection. Therefore, several safety assessments are normally incorporated into the production process of these skin grafts [61]. First, the donor material needs to be screened for blood-borne pathogens and latent viruses. Second, the cell lines need to be fully characterized to minimize, for instance, possible oncogenic potential. Finally, the potential for rejection of non-autologous cells by the recipient's immune response, and the use of immunosuppression therapy, must be addressed early in the development process. The manufacturing and storage of the final product also requires careful consideration. These skin grafts need to be stored by cryopreservation or other techniques that maintain cell viability and efficacy. An extensive overview of the most important commercially available tissue-engineered skin grafts is given in this section and is summarized in Tables 20.1±3. In general, the main disadvantages of these skin grafts are the high costs, the long culture time, the poor mechanical properties, the occurrence of scar contraction, and the scarcity of clinical data to support their tolerability and effectiveness. Furthermore, skin grafts that contain living cells usually have a limited shelf life. The US Food and Drug Administration (FDA) has approved some skin grafts for clinical use in wound healing. However, the role of these skin grafts in the treatment of pressure ulcers remains to be elucidated.

Epidermal Grafts Epicel, developed by Genzyme Biosurgery, is one of the oldest autologous epidermal equivalents. It was first created in 1975, but has been commercially available only since 1988 [64, 66, 67]. For the generation of Epicel a small skin biopsy sample is required from which a cell suspension of epidermal keratinocytes can be obtained [67]. This cell suspension is seeded and cultured on lethally irradiated 3T3 mouse fibroblasts. At the moment the cultures reach confluence, the keratinocyte sheets are released with dispase and attached to a non-adherent gauze dressing [67, 68]. Epicel provides permanent wound coverage and has been used to treat burns [67, 69, 70], chronic leg ulcers [67, 71], and pressure ulcers [67, 72].

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EpiDex, developed by Modex Thrapeutiques, is another autologous epidermal equivalent composed of a keratinocyte sheet [66]. This epidermal equivalent does not rely on skin biopsies, but is generated from the patient's hair. Precursor cells for epidermal keratinocytes can be easily obtained from plucked scalp hair follicles, and these cells retain a high proliferative capacity irrespective of the age of the donor. The engineered keratinocyte sheets have always been fragile, hard to handle, and display unstable attachment without dermal substrate. Fidia Advanced Biopolymers is attempting to remove this disadvantage by providing a film of benzoylated hyaluronic acid as additional dermal equivalent (Laserskin) [73]. This film has periodic perforations through which the keratinocytes can migrate to reach the dermis of the host, and further the film is biodegradable. ConvaTec has also generated autologous keratinocyte sheets on porous films of hyaluronic acid (VivoDerm) [66]. This epidermal graft has mainly been used for burns and chronic wounds, such as venous ulcers [66, 74, 75]. In 1983 Pruniras et al. rendered the culture of keratinocytes more physiological by raising the cultured keratinocytes to the air±liquid interface [76]. By doing so they obtained evidence of a more complete differentiation, as evaluated by morphological criteria. Under the electron microscope, several ultrastructural features reminiscent of those seen in situ could be identified, including tonofilaments, desmosomes, and cell-membrane thickening. The stratum corneum barrier function of the epidermal equivalent could be markedly improved by topical exposure to air. Keratinocytes can be raised to the air±liquid interface by culturing them on dermal substrates or dermal equivalents. Episkin, developed by Episkin

Table 20.1. Epidermal grafts Product name

Reference(s)

Company

Epidermal equivalent

Dermal equivalent

Epicel

[64, 66±72]

Genzyme Biosurgery

Autologous keratinocyte sheet

Non-adherent gauze dressing

EpiDex

[66]

Modex Thrapeutiques

Autologous keratinocyte sheet from hair follicle precursor cells

Not indicated

Laserskin

[73]

Fidia Advanced Biopolymers

Autologous keratinocyte sheet

A porous film of benzoylated hyaluronic acid

VivoDerm

[66, 74±75]

ConvaTec

Autologous keratinocyte sheet

A porous film of hyaluronic acid

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New Tissue Repair Strategies

Fig. 20.1. A histological section of EpiDerm

SNC, is generated by seeding keratinocytes on a dermal substrate composed of a thin bovine collagen type I matrix surfaced with a film of human collagen type IV [77, 78]. MatTek Corporation also uses dermal substrates to expose the keratinocytes to air and generate epidermal grafts. EpiDerm is composed of human keratinocytes that are seeded on cell culture inserts coated with collagen. In Fig. 20.1 a histological image of EpiDerm is shown. SkinEthic, developed by Laboratoire SkinEthic, is also composed of human keratinocytes that are seeded on inert polycarbonate cell culture inserts. These three epidermal equivalents are, however, not employed to treat patients, but are mostly used as diagnostic products for topical irritation, corrosivity and other testing studies [73, 77±81]. The culturing of keratinocytes on dermal equivalents is discussed below in the section `Composite Grafts'.

Dermal Grafts Besides epidermal equivalents, dermal analogues are required to replace the dermis lost in chronic wounds and burns. Transcyte (formerly known as Dermagraft-TC), developed by Advanced Tissue Sciences (ATIS), was the first tissue-engineered dermal equivalent to receive approval by the FDA [64, 67, 73, 82]. For the generation of this graft, neonatal, allogenic fibroblasts are cultured and proliferate on nylon fibres that are embedded into a Silastic layer for 4±6 weeks [66]. After the synthesis of extracellular matrix components and growth factors, the fibroblasts are rendered nonviable by freezing. Transcyte was originally developed as a temporary covering for severe burns [73]. However, it is also used in the treatment of deep partial-thickness burns. A modification of Transcyte is Dermagraft, which recently obtained approval by the FDA [73]. In contrast with Transcyte, this graft does not contain a Silastic layer and is a living dermal equivalent [64]. It can be obtained by culturing human allogenic fibroblasts from neonatal foreskin on a bio-absorbable polyglactin net in a sterile bag with circulating nutrients [64, 66]. These cells attach, multiply, and begin secreting growth factors. Investigation of Dermagraft has shown that it possesses considerable an-

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Dermal Grafts

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Table 20.2. Dermal grafts Product name

References

Company

Epidermal equivalent

Dermal equivalent

Transcyte

[64, 66, 67, 73, 82]

Advanced Tissue Sciences (ATIS)

A Silastic layer

Allogenic, neonatal, foreskin-derived fibroblasts cultured on a nylon scaffold and rendered non-viable after synthesis of extracellular matrix components and growth factors

Dermagraft

[64, 66, 73, 83±85]

Advanced Tissue Sciences (ATIS)

None

Allogenic, neonatal, foreskin-derived fibroblasts cultured on a bio-absorbable, polyglactin scaffold

Alloderm

[64, 66, 74, 86]

Life Cell Corporation

None

An acellular cadaveric dermis with an intact basement membrane

Xenoderm

[66, 74]

Life Cell Corporation

None

An acellular porcine dermis with an intact basement membrane

E-Z-Derm

[66, 67]

WoundCare

None

An acellular porcine dermis with crosslinked collagen

Oasis

[66, 67, 73]

Cook Biotech

None

A collagen matrix obtained from porcine small-intestinal submucosa

Integra

[64, 66, 67]

Integra Life Science Corporation

A bilaminated Silastic membrane

A matrix of bovine collagen and shark glycosaminoglycans

giogenic activity, which is enhanced by the cryopreservation process used to store the product [73, 83±85]. This graft is commercially available for use in diabetic foot ulcers [73]. The living fibroblast collagen matrix can be used alone or as a basis for a skin graft or an autologous skin flap [66]. Alloderm, developed by Life Cell Corporation, is made of salt-processed human cadaveric skin and comprises an acellular dermal matrix and an in-

364

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tact basement membrane complex, without an epidermis [64, 86]. This dermal substrate received FDA approval in 1992 [66]. Alloderm is decellularized, freeze-dried and biochemically stabilized [64]. This dermal graft has been used for the treatment of burns and dermal defects. Alloderm provides a template with natural dermal porosity for regeneration and allows the use of thinner additional grafts. Xenoderm is quite similar to Alloderm. This dermal substrate is developed by the same general process, but with material obtained from porcine skin [66, 74]. E-Z-Derm, developed by WoundCare, is a temporary skin substitute [66, 67]. This dermal substrate is an acellular porcine dermal matrix, in which the porcine collagen has been chemically cross-linked using an aldehyde. It is available as a perforated or a non-perforated dressing attached to a gauze liner that is discarded before application [67]. Oasis, developed by Cook Biotech, is made of material obtained from porcine small intestinal submucosa [66, 67, 73]. The serosa, smooth muscle, and submucosa are removed from this material [66]. The remaining collagenous, three-dimensional matrix serves as a reservoir for cytokines and cell-adhesion molecules, providing a scaffold for tissue growth after implantation. It has been proven that the structure and chemical composition of Oasis support tissue-specific remodelling [66, 67]. Oasis is supplied in hydrated (moist) or lyophilized (dry) sheets. Integra, developed by the Integra Life Science Corporation, is composed of a bilaminated membrane consisting of a Silastic outer covering bonded to a collagen-based dermal equivalent, composed of bovine tendon collagen and shark glycosaminoglycans [64, 66, 67]. In 1996, Integra received FDA approval for use of Integra in burns. The main quality of this material are the pores induced in the matrix by a freeze-drying process that includes cross-linking [66]. At the moment the matrix becomes vascularized, the disposable Silastic layer is removed and can be replaced by a skin graft or combined to an autologous skin flap [66, 67].

Composite Grafts Apligraf, developed by Organogenesis, is a bilayered skin equivalent that received FDA approval in 1998 [64, 66, 67]. This product is composed of both a dermal and an epidermal equivalent, containing living allogenic keratinocytes as well as fibroblasts. To generate Apligraf, human keratinocytes and human dermal fibroblasts are derived from neonatal foreskin and propagated in culture [64]. The dermal equivalent is composed of a mixture of bovine type I collagen and human fibroblasts. After 2 weeks of generating this mixture, a dense fibrous network of newly formed collagen and other matrix components is formed. A suspension of keratinocytes is placed on top of this mixture, to generate the overlying epidermal equivalent. Subsequently, these keratinocytes are exposed to an air±liquid interface to promote keratinocyte differentiation and the formation of a stratum corneum.

a

Composite Grafts

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365

Apligraf resembles human skin histologically and can be thought of as `smart' tissue. It has been shown to have the ability to self-regenerate when injured in vitro, and produces a number of growth factors and cytokines [64, 66]. It is hypothesized that the cells of this tissue-engineered skin can serve the environment into which they are placed, and take `corrective action' by producing the appropriate soluble factors, IL-1, IL-3, IL-6, IL-8, TGF-a, TGF-b, and bFGF [64, 82]. In 2000, Brem et al. performed a clinical trial to test the efficacy of Apligraf in treating pressure ulcers [87]. In pressure ulcers of various durations, the application of Apligraf with the surgical principles used in a traditional skin graft (i.e. skin flap) is successful in producing healing. In patients with pressure ulcers, 13 of the 21 wounds healed in an average of 29 days. All wounds that did not heal in this series occurred in patients who had an additional stage IV ulcer or a wound with exposed bone. One possible limitation of this study is that it was a nonrandomized study with no placebo group. However, it had been established earlier in separate prospective, randomized, placebo-controlled studies that Apligraf accelerates closure of two types of chronic wounds (i.e. venous and diabetic) [87±90]. The data presented in the study performed by Brem et al. indicate that when infection is controlled by debridement and other appropriate therapy, biological intervention with Apligraf provides a choice that assures lack of progression in pressure ulcers [87]. Orcel, developed by Ortec International, consists of allogenic fibroblasts and keratinocytes grown in vitro and seeded on the reverse side of a bilayered matrix of bovine collagen [66]. This bilayered skin equivalent has

Table 20.3. Composite grafts Product name

References

Company

Epidermal equivalent

Dermal equivalent

Apligraf

[64, 66, 67, 87±90]

Organogenesis

Allogenic, neonatal, foreskin-derived keratinocytes cultured on top of the dermal equivalent and exposed to air to promote keratinocyte differentiation and formation of a stratum corneum

Allogenic, neonatal, foreskin-derived fibroblasts cultured with bovine type I collagen to form a dense network of newly formed extracellular matrix components

Orcel

[66, 73]

Ortec International

Allogenic keratinocytes cultured on the non-porous upper side of the dermal equivalent

Allogenic fibroblast cultured in a porous cross-linked bovine collagen sponge matrix

366

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New Tissue Repair Strategies

also obtained FDA approval [73]. The collagen matrix of this skin equivalent consists of a cross-linked bovine collagen sponge with an overlay of pepsinized insoluble collagen [66]. The keratinocytes are seeded on the insoluble collagen and the fibroblasts are seeded on the underside of the porous sponge. Orcel has been used in the treatment of epidermolysis bullosa (EB). Ortec International has also submitted a pre-market approval application for the use of Orcel in treating skin graft donor sites and has performed successful clinical trials in diabetic and venous ulcers [73]. The abundance of engineered skin grafts indicates that substantial progress has already been made in the field of skin tissue engineering. Nevertheless, several drawbacks need to be overcome to generate grafts mimicking normal human skin with high accuracy, which might also be applicable for effective healing of pressure ulcers. In particular the mechanical properties and integrity of engineered skin grafts remain to be optimized, as these properties are essential for bearing the prolonged loads applied to the human body under predisposing conditions for pressure ulcer development. Therefore, current research in the field of skin tissue engineering focuses, for instance, on improving the skin barrier properties [91±93] and on improving the structural interaction of the epidermal and the dermal equivalent of composite grafts [94, 95].

Gene Therapy The skin is an attractive target for gene therapy because it is easily accessible and shows great potential as an ectopic site for delivery of protein (e.g. growth factors and cytokines) in vivo [96]. The application of gene therapy to the field of wound healing is still in its infancy, but it may have potential. The purpose of gene therapy in this setting is either to promote wound healing or to reduce the healing complications that lead to scarring, keloid formation or chronic ulceration. Dependent on the type and the severity of the wound, different gene delivery strategies can be used to promote wound healing. The most appropriate treatment for large wounds, which are in need of skin replacements, is the use of genetically modified skin grafts. In this case, cells need to be cultured, genetically modified in vitro, and used to engineer a skin graft that can be transplanted in the denuded wound areas to facilitate in situ tissue regeneration. Cells can be genetically engineered to express a variety of molecules, including growth factors that induce cell growth/differentiation or cytokines that prevent immunological reaction to the implant. On the other hand, smaller wounds may be amenable to in vivo gene delivery using a variety of approaches including gene injection, gene gun, microseeding, and liposomal gene delivery. The results of preclinical studies of gene therapy for wound healing are promising, but numerous clinical trials have to be performed to determine the real effectiveness of this new treatment in healing chronic wounds, such as pressure ulcers.

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Gene Therapy

z

367

The majority of gene therapy studies in wound healing used recombinant retroviruses to modify the epidermal keratinocytes of engineered skin grafts [96]. In 1998, Eming et al. showed that PDGF-A overexpression improved the performance of composite grafts when transplanted to fullthickness wounds on athymic mice [96, 97]. Seven days after transplantation, these grafts demonstrated reduced wound contraction and increased dermal cell density in comparison with unmodified control grafts. Earlier, it had been demonstrated by Eming et al. that transplantation of genetically modified epidermal grafts overexpressing PDGF-A increased the growth and vascularization of the underlying dermal tissue [96, 98]. These results demonstrate the feasibility of using genetically modified skin grafts overexpressing PDGF-A to modulate wound healing. In 2000, Supp et al. used a recombinant retrovirus to transfer the gene encoding for VEGF to epidermal keratinocytes of composite grafts [96, 99]. VEGF-modified and unmodified composite grafts were transplanted to full-thickness wounds on athymic mice, and elevated VEGF mRNA expression was detected in the modified grafts for at least 2 weeks after surgery. The VEGF-modified grafts further exhibited increased numbers of dermal blood vessels and decreased time to vascularization compared with the unmodified control grafts. Recently, Supp et al. demonstrated that the VEGF-modified grafts showed reduced contraction, which suggest more stable engraftment and better tissue development [96, 100]. Furthermore, an altered spatial distribution of blood vessels in the VEGF-modified grafts was demonstrated with more vessels in the upper epidermis, which is in close proximity to the modified epidermal cells. These results suggest that VEGF overexpression in genetically modified skin grafts can contribute to improved healing of full-thickness wounds. Many technologies have also been developed for in vivo gene delivery to the skin [96]. The efficiency of these gene delivery methods for the treatment of (chronic) wounds has been determined in various preclinical studies. In 1999, Liechty et al. demonstrated that the application of a single dose of PDGF-B-encoding adenovirus on wounds in ischaemic rabbit ear, which have a 60% delay in healing, enhanced wound healing compared with placebo-treated control wounds, topical application of high concentrations of the PDGF-B protein, and placebo-treated non-ischaemic wounds [96, 101]. These results indicate that adenoviral-mediated gene transfer of PDGF-B overcomes the ischaemic defect in wound healing and, therefore, offers promise in the treatment of chronic non-healing wounds. A b-galactosidase-encoding adenovirus was also applied on wounds in the ischaemic rabbit ear [96, 102]. However, wound reepithelization was impaired in the b-galactosidase treated wounds compared with placebo-treated control wounds. This adverse effect is possibly a result of an acute inflammatory response to the adenoviral particles [96]. Therefore, selection of the proper transgene with appropriate biological activity in wound healing seems essential to avoid an adverse effect on the healing response. The gene gun or particle-mediated gene transfer is another gene delivery method that has been evaluated for wound healing [96]. Propelled from a ballistic device,

368

z

New Tissue Repair Strategies

gold microparticles conjugated with DNA penetrate cell membranes to transfect the cells of the wounded skin. It has been shown that the microprojectile delivery of EGF, TGF-b and PDGF in the wound bed enhances wound healing rates and increases wound tensile strength [96, 103±105]. Microseeding is also being studied for gene delivery to wounded skin [96]. This method delivers DNA through a set of solid oscillating microneedles which are able to penetrate to various depths of the tissue. Eriksson et al. demonstrated that delivery of an EGF-encoding plasmid to partial thickness wounds in pigs via microseeding is more efficient than gene delivery by a single injection or even the gene gun [96, 106]. Besides physical methods, chemical methods of gene delivery have been employed for wound healing, such as liposomal gene delivery. Sun et al. showed that liposomal delivery of the FGF-1 gene in wounds of diabetic mice promoted wound healing in three administrations, compared with 15 administrations required to achieve a similar biological effect by the delivery of the protein [96, 107]. In addition to wound-healing technologies that introduce genes into target cells, antisense oligonucleotides (ODN) have been used to block unwanted gene functions [96]. This method allows the specific inhibition of the biosynthesis of a protein by adding to the cells a synthetic nucleotide complementary to a portion of the mRNA encoding for the protein [108]. The ODN penetrate into the cell and are thought to hybridize and block the recognition of the normal message [108, 109]. Choi et al. demonstrated that topical application of antisense ODN targeted to TGF-b1 mRNA reduced scarring compared with the control wound site on a mouse [96, 110]. This result indicates that antisense TGF-b1 ODN could be used for ameliorating scar formation during wound healing.

Future Perspectives With the ongoing progress in biotechnology and life sciences a new paradigm for treating chronic wounds has emerged. New treatments are being developed that better address the pathogenic abnormalities of chronic wounds, such as topical application of growth factors, tissue-engineered skin grafts, and gene therapy. Despite their current shortcomings and limited clinical evaluation these new therapies have great potential for healing pressure ulcers. For widespread clinical application, however, conclusive studies regarding their long-term effects and cost-effectiveness need to be performed. In addition, ethical considerations apply when using, for instance, genetically modified or non-autologous cells as well as their products.

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References

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77. Ponec M, Boelsma E, Weerheim A, Mulder A, Bouwstra J, Mommaas M (2000) Lipid and ultrastructural characterization of reconstructed skin models. Int J Pharm 203:211±225 78. Ponec M, Boelsma E, Gibbs S, Mommaas M (2002) Characterization of reconstructed skin models. Skin Pharmacol Appl Skin Physiol 15 [Suppl 1]:4±17 79. Coquette A, Berna N, Vandenbosch A, Rosdy M, De Wever B, Poumay Y (2003) Analysis of interleukin-1alpha (IL-1alpha) and interleukin-8 (IL-8) expression and release in in vitro reconstructed human epidermis for the prediction of in vivo skin irritation and/or sensitization. Toxicol In Vitro 17:311±321 80. Faller C, Bracher M (2002) Reconstructed skin kits: reproducibility of cutaneous irritancy testing. Skin Pharmacol Appl Skin Physiol 15 [Suppl 1]:74±91 81. Gibbs S, Vietsch H, Meier U, Ponec M (2002) Effect of skin barrier competence on SLS and water-induced IL-1alpha expression. Exp Dermatol 11:217±223 82. Eaglstein WH, Falanga V (1998) Tissue engineering for skin: an update. J Am Acad Dermatol 39:1007±1010 83. Mansbridge JN, Liu K, Pinney RE, Patch R, Ratcliffe A, Naughton GK (1999) Growth factors secreted by fibroblasts: role in healing diabetic foot ulcers. Diabetes Obes Metab 1:265±279 84. Pinney E, Liu K, Sheeman B, Mansbridge J (2000) J. Human three-dimensional fibroblast cultures express angiogenic activity. J Cell Physiol 183:74±82 85. Liu K, Yang Y, Mansbridge J (2000) Comparison of the stress response to cryopreservation in monolayer and three-dimensional human fibroblast cultures: stress proteins, MAP kinases, and growth factor gene expression. Tissue Eng 6:539±554 86. Phillips TJ (1998) New skin for old: developments in biological skin substitutes. Arch Dermatol 134:344±349 87. Brem H, Balledux J, Bloom T, Kerstein MD, Hollier L (2000) Healing of diabetic foot ulcers and pressure ulcers with human skin equivalent: a new paradigm in wound healing. Arch Surg 135:627±634 88. Falanga V, Sabolinski M (1999) A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen 7:201±207 89. Falanga V (1999) How to use Apligraf to treat venous ulcers. Skin Aging 25:30±36 90. Pham HT, Rosenblum BI, Lyons TE, et al. (1999) Evaluation of a human skin equivalent for the treatment of diabetic foot ulcers in a prospective, randomized, clinical trial. Wounds 11:79±86 91. Ponec M, Wauben-Penris PJ, Burger A, Kempenaar J, Bodde HE (1990) Nitroglycerin and sucrose permeability as quality markers for reconstructed human epidermis. Skin Pharmacol 3:126±135 92. Ponec M, Weerheim A, Kempenaar J, Mulder A, Gooris GS, Bouwstra J, Mommaas AM (1997) The formation of competent barrier lipids in reconstructed human epidermis requires the presence of vitamin C. J Invest Dermatol 109:348±355 93. Ponec M, Gibbs S, Pilgram G, Boelsma E, Koerten H, Bouwstra J, Mommaas M (2001) Barrier function in reconstructed epidermis and its resemblance to native human skin. Skin Pharmacol Appl Skin Physiol 14 [Suppl 1]:63±71 94. Medalie DA, Eming SA, Collins ME, Tompkins RG, Yarmush ML, Morgan JR (1997) Differences in dermal analogs influence subsequent pigmentation, epidermal differentiation, basement membrane, and rete ridge formation of transplanted composite skin grafts. Transplantation 64:454±465

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95. Guo M, Grinnell F (1989) Basement membrane and human epidermal differentiation in vitro. J Invest Dermatol 93:372±378 96. Andreadis ST (2004) Gene transfer to epidermal stem cells: implications for tissue engineering. Expert Opin Biol Ther 4:783±800 97. Eming SA, Medalie DA, Tompkins RG, Yarmush ML, Morgan JR (1998) Genetically modified human keratinocytes overexpressing PDGF-A enhance the performance of a composite skin graft. Hum Gene Ther 9:529±539 98. Eming SA, Lee J, Snow RG, Tompkins RG, Yarmush ML, Morgan JR (1995) Genetically modified human epidermis overexpressing PDGF-A directs the development of a cellular and vascular connective tissue stroma when transplanted to athymic mice ± implications for the use of genetically modified keratinocytes to modulate dermal regeneration. J Invest Dermatol 105:756±763 99. Supp DM, Supp AP, Bell SM, Boyce ST (2000) Enhanced vascularization of cultured skin substitutes genetically modified to overexpress vascular endothelial growth factor. J Invest Dermatol 114:5±13 100. Supp DM, Boyce ST (2002) Overexpression of vascular endothelial growth factor accelerates early vascularization and improves healing of genetically modified cultured skin substitutes. J Burn Care Rehabil 23:10±20 101. Liechty KW, Nesbit M, Herlyn M, Radu A, Adzick NS, Crombleholme TM (1999) Adenoviral-mediated overexpression of platelet-derived growth factor-B corrects ischemic impaired wound healing. J Invest Dermatol 113:375± 383 102. Liechty KW, Sablich TJ, Adzick NS, Crombleholme TM (1999) Recombinant adenoviral mediated gene transfer in ischemic impaired wound healing. Wound Repair Regen 7:148±153 103. Andree C, Swain WF, Page CP, Macklin MD, Slama J, Hatzis D, Eriksson E (1994) In vivo transfer and expression of a human epidermal growth factor gene accelerates wound repair. Proc Natl Acad Sci USA 91:12188±12192 104. Benn SI, Whitsitt JS, Broadley KN, Nanney LB, Perkins D, He L, Patel M, Morgan JR, Swain WF, Davidson JM (1996) Particle-mediated gene transfer with transforming growth factor-beta1 cDNAs enhances wound repair in rat skin. J Clin Invest 98:2894±2902 105. Eming SA, Whitsitt JS, He L, Krieg T, Morgan JR, Davidson JM (1999) Particle-mediated gene transfer of PDGF isoforms promotes wound repair. J Invest Dermatol 112:297±302 106. Eriksson E, Yao F, Svensjo T, Winkler T, Slama J, Macklin MD, Andree C, McGregor M, Hinshaw V, Swain WF (1998) In vivo gene transfer to skin and wound by microseeding. J Surg Res 78:85±91 107. Sun L, Xu L, Chang H, Henry FA, Miller RM, Harmon JM, Nielsen TB (1997) Transfection with aFGF cDNA improves wound healing. J Invest Dermatol 108:313±318 108. Kim HM, Choi DH, Lee YM (1998) Inhibition of wound-induced expression of transforming growth factor-beta 1 mRNA by its antisense oligonucleotides. Pharmacol Res 37:289±293 109. Thierry AR, Rahman A, Dritschilo A (1992) Liposomal delivery as a new approach to transport antisense oligonucleotides. In Erickson R, Izant JG, editors. Gene regulation: biology of antisense RNA and DNA. Raven Press, New York, pp 147±161 110. Choi BM, Kwak HJ, Jun CD, Park SD, Kim KY, Kim HR, Chung HT (1996) Control of scarring in adult wounds using antisense transforming growth factor-beta 1 oligodeoxynucleotides. Immunol Cell Biol 74:144±150

Subject Index

A Absorption 248 Acetylcholine 90 Acrocyanosis 97 Actin 249 Action potential 90 Adaptation 132, 176, 274, 275 Adaptive capacity 156 Adipocytes 249 Adipose tissue 94, 250 Adjuvant therapy 46 Aerobic anoxia 238 Aetiology 1, 2, 152, 187, 287 Agarose 293 Ageing of skin see skin Agency for Health Care Policy and Research (AHCPR) 38, 42 AHCPR see Agency for Health Care Policy and Research Albumin 99, 247 Allopurinol 169, 196, 214 American Medical Directors Association 38 American Spinal Injuries Association 73 Amino acid 175 Ammonia 176 Anaerobic glycolysis 112 Anaerobic metabolism 258 Anaesthesia 188 Angiogenesis 355 Animal experiment 163 Animal model 187 ± study 318 Anisotropy 164, 289 Anoxia 297 Antioxidant 208 Apoptosis 207, 209, 215, 216, 291, 298 Ascorbic acid see vitamin C

ATP 270 Atrophy 73, 94, 189 Autonomic dysreflexia

74

B Bed ± air-fluidized 42 ± circulating air overlays 42 ± fluidised-bead 55 ± low-air-loss 55 Benchmarking incidence 30 Bilirubin 210 Biochemistry 278 Blanch response 278 Blister 174 ± formation 131 Blunting 264 Body Mass Index 57 Bony promince 41, 53, 151 Buttock 151 C C2C12 cells 289, 291 Ca2+ 249 Calcein-AM 291 Carbonic anhydrase 259 Cardiovascular dysfunction 129 Case study 25 Caspase 215 Catabolic process 176 Catalase 196 Cell line 288 Cell metabolism 235 Cellulites 26 Chondroitin 250 Chromatography 251 Chronic inflammation 355 Classification system 12 Cleansing 44

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Subject Index

Clearance 167 Clinical practice guidelines 37 Clothing 59 Collagen 52, 166, 171, 250 Computer model 3 Computer-aided optimization 149 Confocal microscope 289 Conservation laws 234 ± mass 234 Contact element 137 Contrast agent 319 Convection 233, 234, 242, 245 Costs 23, 35, 98 Creatine 331 Creatine kinase 298 Creep 306 Cross-link 171 CT scanning 318 Cystine 211 Cytokine 169, 206, 209, 354 Cytoplasm 249 Cytoskeleton 5, 287 D Damage criteria 154 Damage evolution 156 Dartec 291 Debridement 44, 45, 80, 99, 354 Deferoxamine 169, 196 Denervation 190 Dermal graft ± Alloderm 363 ± Apligraf 365 ± Dermagraft 363 ± E-Z-derm 364 ± Integra 364 ± Oasis 364 ± Orcel 365 ± Transcyte 363 Dermal papillae 272 Dermatan sulphate 173 Dermis 166, 263 DEXA 94 Dextran 254 Diabetes 101, 129, 188, 268 Diabetic orthosis 51 Diaphragm transducer 52 Differentiation medium 294 Diffusion 233 Dilation 273 Dimensional analysis 152

Dimethylsulfoxide 196 Direct current 101 Diurnal change 135, 136 Donnan osmosis 252 Doppler flowmeter (see also Laser Doppler flowmetry) 191, 199, 268, 278, 309, 310 Dressing 46 E Echo time 320 Effacement 264 Elastin 166, 171, 174, 250, 263 Elastography 304 Electrical stimulation (ES) 89 Endothelium 240, 246, 249 Endurance exercise 90 Engineered skin see skin Epidermal cells 99 Epidermal graft ± Epicel 361 ± EpiDerm 362 ± EpiDex 361 ± Episkin 361 ± SkinEthic 363 ± VivoDerm 361 Epidermal-dermal junction 166 Epidermis 165, 210, 263 Epithelization 355 EPUAP see European Pressure Ulcer Advisory Panel Ergometer 90 Erythema 45, 271, 278 ± blanchable 178 ± non-blanchable 178 ES see electrical stimulation Ethics 163, 288 European Pressure Ulcer Advisory Panel (EPUAP) 38, 65, 80 Extracellular matrix 290 Extravasation 268 Extrinsic factor 37, 73 F Faeces 176 Fenestration 244 Fenton reaction 207, 209 Fibrinolytic activity 279 Fibroblast 99 Fibroplasia 355

a Fick's first law 236 Finite-element model 150 Fixed skin 188 Flaccid paralysis 79, 89 Fluorescence 254 ± probes 294 Free fluid phase 252 Free radical 99, 162, 195, 205, 206, 270 Friction 131 Frictional forces 276 Frictionless contact 151 Fuzzy rat 268 G Gangrene 100 Gene therapy 354, 366 Glutathione 195, 209, 211 Gluteal muscle 187 Gluteal region 94 Gluteus muscle 192 Glycocalyx 250 Glycosaminoglycan 253 Granulation tissue 44, 99, 355 Granulocytes 169 Growth factor 354, 357 ± NGF 358 ± PDGF-BB 357 ± TGF-b3 358 Guidelines 37 ± AHCPR 31 ± NICE 24 H Haber-Weiss reaction 207 Haemoglobin 44, 236 Haemorrhage 321 Haemostasis 354 Heel ulcer 265 Hierarchical aproach 289 Hierarchy 6 Histamine 249 Histochemical change 90 Hyaline degeneration 268 Hyaluronan 250 Hyaluronic acid 173 Hydraulic conductivity 244, 255 Hydraulic permeability 244 Hydrogen peroxide 169, 196, 206 Hydrophilic solutes 240, 245

Subject Index

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377

Hydrophilics 249 Hydroxyl radical 207 Hyperaemia 109, 177, 235, 236, 269, 278 Hypertrophy 90 Hypotension 96 Hypotrichotic fuzzy rat 265 Hypoxia 169 Hysteresis 55, 164, 306 I Ibuprofen 197 IL (Interleukin) 208 Imaging technique 158 In vitro skin 132 Incidence 13, 35, 264 Incontinence 176 ± faecal 25, 28 Infection 26 Infiltration 268 Inflammation 162, 169, 249, 268, 321, 354 Intercellular cleft 244 Interface liner 135 Interleukin see IL Interstitial space 233 Interstition 5 Interstitium 249, 252 Intersubject variability 56 Intestitial fluid (ISF) 251, 252 Intrinsic factor 37, 73, 149, 161 Ischaemia 1, 4, 52, 109, 130, 161, 205, 209, 213, 269, 287, 346 Ischaemia-reperfusion injury 269 Ischial tuberosity 37, 43, 57, 89, 167, 187, 193, 296 ISF see interstitial fluid K Keratin 166 Keratinocytes 218, 263 L Lactate 110, 113, 220, 331 Lactic acid 258 Langerhans' cells 169, 174, 279 Large pore hypothesis 243 Laser Doppler flowmetry see also Doppler flowmeter) 110, 139, 277

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Subject Index

Limb amputation 129 Lipolysis 236 Lipophobics 249 Litigation 24, 27, 61 Load-bearing capacity 4 Loading 1 ± duration 1 ± magnitude 1 Loose skin see skin Lymph 97, 248, 250, 254 Lymph vessel 233 Lymphatics 168, 175, 178, 250, 253, 257, 295 ± drainage 4, 109 Lysine 175 Lysyl hydroxylase 175 M Macromolecule 242 Macrophages 99, 206, 355 Magnetic field 98 Magnetic resonance elastography 329 Magnetic resonance imaging see MRI Magnetic resonance spectroscopy 318, 330 Magnitude 1 Malonyldialdehyde 197 Mannequin 65 Mast cells 249 Matrigel 293 Matrix metalloprotease see MMP Medico-legal implication 23 Mesh generator 152 Mesh-generation 138 Mesoscopy 155 Metabolic inhibitor 243 Metabolic process 158 Metabolic rate 235 Metabolic stress 212 Metabolism 162, 198, 330 ± aerobic 235 ± anaerobic 235, 236 Metabolites 278 Microcirculation 233, 342 ± cutaneous 343 Micromanipulator 289 Microscale optical probe 340 Microvascular flow 348 Microvascular pressure 248 MMP (matrix metalloprotease) 218, 219

Moisture 28, 40 Mongrel dog 169 Monocytes 206, 354 Morphology 179 Motor neuron 90 MRI (magnetic resonance imaging) 150, 156, 199, 297, 317 ± arterial spin labelling 326 ± diffusion-weighted 318, 324 ± perfusion 318, 326 ± T1-weighted 321 ± T2-weighted 155, 201, 321 ± tagging 201, 318, 323 Mucopolysaccharides 263 Multi-level finite-element 156 Multiple sclerosis 59 Multi-scale approach 155 Muscular atrophy 93 Myeloperoxidase 197 Myoblasts 288 Myocytes 169 Myofibre 288 Myoglobin 298 Myosin 249 Myotube 288, 290 N NADH 206 National Health Service 23, 27 National Pressure Ulcer Advisory Panel (NPUAP) 30. 38, 45, 80 Necrosis 3, 35, 99, 163, 270, 291, 298 Necrotic tissue 44 Neutrophils 99, 198, 206, 220, 270, 271, 354 Nitric oxide 207, 214, 249 Non-blancheable discolouration 12 Normoxia 298 NPUAP see National Pressure Ulcer Advisory Panel Nutrient molecule 233 Nutrition 98, 274 Nutritional deficit 41 Nutritional status 37 O Occlusion of blood vessels 35 Oedema 99, 271, 273, 321 Oncotic pressure 245 Organ culture model 273

a Orthotics 62 Osmotic pressure 245, 247, 252 Osmotic swelling 153 Osteomyelitis 318 Oxandrolone 85 Oxford Pressure Monitor 77, 117, 306 Oxidative stress 205, 270 P Panniculus carnosus 163 Papillary dermis 272 Papillary layer 166, 178, 263 Papillary loop 346 Parallel processing 152 Paralysed muscle 90 Paraplegia 188, 268, 297 Paraplegics 51, 175 Partial pressure 277 ± CO2 237 ± O 96 ± PO2 139, 236, 237, 239, 270, 309 ± TcPCO2 112 ± TcPO2 60, 77, 79, 84, 110, 112, 165, 220, 311 Pathology 58 Pathophysiology 256 Pathway 3 Patient-turning regimen 294 PEBBLE sensor 350 Peclet number 246 Perimysium 250 Permeability 244, 249 Peroxisomes 206 Peroxyl radical 207 Phagocytic cells 206 Phantom 65 Phosphocreatine 331 Photobleaching 341 Piezo-actuator 289 Pig ± hairless 268 Plasma protein 248 Porcine skin 268 Post mortem 272 Posture 64 Potassium 110 Practice guidelines 27 Precursor cells 288 PrePURSE study 15, 17 Pressure 1 ± capillary 1

Subject Index

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379

± hydrostatic 150, 192, 253 ± index 64 ± interface 1, 52, 60, 132, 133, 307 ± interstitial 60 ± ± fluid 252 ± lymphatic 253 ± perfusion 95 ± redistribution 27 ± relief 98 ± seating 97 ± time curves 187 ± treshold 131 Prevalence 1, 30 ± recordings 11 Proliferation 354 Prophylaxis 95 Propidium iodide 289 Proteoglycan 171, 173, 269 Proton density 320 Pulsed current: monophasic 92 Pulsed direct current: high-voltage 92 Purines 116, 117, 121 ± allantoin 116 ± hypoxanthine 116, 117 ± inosine 116, 117 ± uric acid 116 ± xanthine 116, 117 Q Quadriceps 97 Quality of life 1 Questionnaire 12 R Rat model 265 Rat tail 254 Recovery time 278 Reflection coefficient 244 Remodelling 132, 354 Reperfusion 205, 213, 269, 287, 295, 346 ± injury 162, 195 Representative volume element 156 Residual limb shape 135 Resistance exercise 90 Reticular dermis 175 Reticular layer 166, 263 Reticulin fibril 172 Retrospective study 25 Risk assessment tool 1, 277

380

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Subject Index

± Braden 27 ± Norton 27 ± Waterlow 17, 27 Risk factor 35, 51 S Sacral ulcer 265 Sacrum 167, 58 Scales ± Braden 40 ± Norton 40, 42 ± Waterlow 40 SCI see spinal cord injury Seat metabolites 110 Sensitivity 26 ± analysis 151 Sensor ± electrochemical 337 ± fibre-optic 340 ± optical 337 ± TcPO2 electrode 339 Sensory paralysis 75 Sensory perception 37 Sepsis 26 Serum albumin 44 Shape change 136 Shear 271, 275, 276 ± forces 195 ± sensor 308 ± simple 153 Signal delay time 320 Skin ± aging 174 ± colour 278 ± engineered 354 ± loose 163, 188 ± necrosis 274 ± organ culture 265 Socket design 134 Spasticity 79 Specificity 26 Spectrophotometry 110 Spectroscopy 277 Spin magnetization 319 Spina bifida 59, 308 Spinal cord injury (SCI) 59, 89, 73, 177, 318 Stem cells 219 Stratum ± basale 263 ± corneum 175, 195, 210, 263, 344, 361

± granulosum 263 ± lucidum 263 ± spinosum 263 Stress 4 ± interface 129, 131, 133, 136, 137, 138, 140 ± von Mises 4, 150 Sub-papillary plexus 342 Superoxide 206 ± dismutase 196 Surgery ± myocutaneous flap 132 Surgical patient 15 Susceptibility 73, 153, 268 Sustained deformation 4 Sweat 132, 205, 220, 278 ± gland 264 T Talley-Scimedics Pressure Evaluator 305 TE 320 Temperature 198, 271 Tetanic contraction 90 Tetraplegia 94, 97 Thallium 96 Theoretical model 149 Therapy ± laser 98 ± oxygen 98 Thermal recovery time 139 Thermography 277 Thrombosis 95, 270 Tibialis anterior 165, 318, 322 TIPE System 306 Tissue ± engineering 6, 187, 288, 298, 359 ± necrosis 130 ± reflectance spectroscopy 309 ± repair 91 ± tolerance 37, 157, 161, 174 ± viability 162 Tissue-engineered ± construct 155 ± model 265 ± skin 359 TNF-a 208 Tocopherol 210 Total contact socket 130 TR 320 Tracer 96, 254

a Transcutaneous electrical nerve stimulation 96 Transection 189 Transport ± metabolites 233, 234 ± nutrient 233, 234 ± oxygen 236 Trochanter 41±43, 187, 191, 193, 272, 297 Tuberosity, ischial 4 Tubulin 279 U Ultra-filtration 245, 246 Ultrasound 98, 102 ± imaging 302 Uniaxial compression 153 Urea 110, 113 Uric acid 210 Urine 176 V Vascular atrophy 95 Vascular endothelial growth factor see VEGF Vascularity 74 Vasodilation 96, 278 VEGF (vascular endothelial growth factor) 220 Venous pressure 248 Vesicle 243 Visco-elasticity 164, 169 Vision Engineering Research Group 302

Subject Index Vital imaging 6 Vitamin C 209, 212 Vitamin E 169, 196, 196, 209 W Wate-soluble solutes ± amino acid 240 ± glucose 240 ± lactic acid 240 ± pyruvic acid 240 Wheelchair 150 Wick catheter 60, 164, 252 Wound ± assessment 302 ± bed preparation 356 ± dimension 302 ± dressing 98, 354 ± fluid 205 ± healing 217, 354 Wound Healing Society 356 X Xanthine dehydrogenase 206 Xanthine oxidase (XO) 213 Xenon 96 XO see xanthine oxidase X-rays 302 Z Zinc 212

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381